Publications by authors named "Lynn Wang"

80 Publications

Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication.

Blood Cancer J 2021 Feb 18;11(2):39. Epub 2021 Feb 18.

Fox Chase Cancer Center, Philadelphia, PA, USA.

Ibrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients' actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease.
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http://dx.doi.org/10.1038/s41408-021-00429-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893066PMC
February 2021

Inhibition of B-cell receptor signaling disrupts cell adhesion in mantle cell lymphoma via RAC2.

Blood Adv 2021 Jan;5(1):185-197

Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA.

Inhibition of the B-cell receptor (BCR) signaling pathway is highly effective in B-cell neoplasia through Bruton tyrosine kinase inhibition by ibrutinib. Ibrutinib also disrupts cell adhesion between a tumor and its microenvironment. However, it is largely unknown how BCR signaling is linked to cell adhesion. We observed that intrinsic sensitivities of mantle cell lymphoma (MCL) cell lines to ibrutinib correlated well with their cell adhesion phenotype. RNA-sequencing revealed that BCR and cell adhesion signatures were simultaneously downregulated by ibrutinib in the ibrutinib-sensitive, but not ibrutinib-resistant, cells. Among the differentially expressed genes, RAC2, part of the BCR signature and a known regulator of cell adhesion, was downregulated at both the RNA and protein levels by ibrutinib only in sensitive cells. RAC2 physically associated with B-cell linker protein (BLNK), a BCR adaptor molecule, uniquely in sensitive cells. RAC2 reduction using RNA interference and CRISPR impaired cell adhesion, whereas RAC2 overexpression reversed ibrutinib-induced cell adhesion impairment. In a xenograft mouse model, mice treated with ibrutinib exhibited slower tumor growth, with reduced RAC2 expression in tissue. Finally, RAC2 was expressed in ∼65% of human primary MCL tumors, and RAC2 suppression by ibrutinib resulted in cell adhesion impairment. These findings, made with cell lines, a xenograft model, and human primary lymphoma tumors, uncover a novel link between BCR signaling and cell adhesion. This study highlights the importance of RAC2 and cell adhesion in MCL pathogenesis and drug development.
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http://dx.doi.org/10.1182/bloodadvances.2020001665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805322PMC
January 2021

TCF-1 regulates HIV-specific CD8+ T cell expansion capacity.

JCI Insight 2021 Feb 8;6(3). Epub 2021 Feb 8.

Department of Medicine, UCSF, San Francisco, California, USA.

Although many HIV cure strategies seek to expand HIV-specific CD8+ T cells to control the virus, all are likely to fail if cellular exhaustion is not prevented. A loss in stem-like memory properties (i.e., the ability to proliferate and generate secondary effector cells) is a key feature of exhaustion; little is known, however, about how these properties are regulated in human virus-specific CD8+ T cells. We found that virus-specific CD8+ T cells from humans and nonhuman primates naturally controlling HIV/SIV infection express more of the transcription factor TCF-1 than noncontrollers. HIV-specific CD8+ T cell TCF-1 expression correlated with memory marker expression and expansion capacity and declined with antigenic stimulation. CRISPR-Cas9 editing of TCF-1 in human primary T cells demonstrated a direct role in regulating expansion capacity. Collectively, these data suggest that TCF-1 contributes to the regulation of the stem-like memory property of secondary expansion capacity of HIV-specific CD8+ T cells, and they provide a rationale for exploring the enhancement of this pathway in T cell-based therapeutic strategies for HIV.
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http://dx.doi.org/10.1172/jci.insight.136648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934879PMC
February 2021

Prognostic and Predictive Molecular Biomarkers in Chronic Lymphocytic Leukemia.

J Mol Diagn 2020 09 29;22(9):1114-1125. Epub 2020 Jun 29.

Department of Pathology, Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Electronic address:

Chronic lymphocytic leukemia (CLL) is a malignancy of B cells with a variable clinical course. Prognostication is important to place patients into different risk categories for guiding decisions on clinical management, to treat or not to treat. Although several clinical, cytogenetic, and molecular parameters have been established, in the past decade, a tremendous understanding of molecular lesions has been obtained with the advent of high-throughput sequencing. Meanwhile, rapid advances in the understanding of the CLL oncogenic pathways have led to the development of small-molecule targeting signal transducers, Bruton tyrosine kinase and phosphatidylinositol 3-kinase, as well as anti-apoptotic protein BCL2 apoptosis regulator. After an initial response to these targeted therapies, some patients develop resistance and experience disease progression. Novel gene mutations have been identified that account for some of the drug resistance mechanisms. This article focuses on the prognostic and predictive molecular biomarkers in CLL relevant to the molecular pathology practice, beginning with a review of well-established prognostic markers that have already been incorporated into major clinical guidelines, which will be followed by a discussion of emerging biomarkers that are expected to impact clinical practice soon in the future. Special emphasis will be put on predictive biomarkers related to newer targeted therapies in hopes that this review will serve as a useful reference for molecular diagnostic professionals, clinicians, as well as laboratory investigators and trainees.
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http://dx.doi.org/10.1016/j.jmoldx.2020.06.004DOI Listing
September 2020

Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer.

Cell 2020 04;181(2):442-459.e29

Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. Electronic address:

Single-cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application toward dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune and stromal populations from colorectal cancer patients, identifying specific macrophage and conventional dendritic cell (cDC) subsets as key mediators of cellular cross-talk in the tumor microenvironment. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated a cDC population and increased Bhlhe40 Th1-like cells and CD8 memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing.
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http://dx.doi.org/10.1016/j.cell.2020.03.048DOI Listing
April 2020

TMEM16B Calcium-Activated Chloride Channels Regulate Action Potential Firing in Lateral Septum and Aggression in Male Mice.

J Neurosci 2019 09 18;39(36):7102-7117. Epub 2019 Jul 18.

Department of Physiology, University of California San Francisco, San Francisco, California 94143,

The lateral septum (LS) plays an important role in regulating aggression. It is well recognized that LS lesions lead to a dramatic increase in aggressive behaviors. A better understanding of LS neurophysiology and its functional output is therefore important to assess LS involvement in regulating aggression. The LS is a heterogeneous structure that maintains inputs and outputs with multiple brain regions, and is also divided into subregions that innervate one another. Thus, it is challenging to identify the exact cell type and projections for characterization. In this study, we determined the expression pattern of the calcium-activated chloride channel, TMEM16B, in the LS of both male and female mice. We then investigated the physiological contribution of the calcium-activated chloride channel to LS neuronal signaling. By performing whole-cell patch-clamp recording, we showed that TMEM16B alters neurotransmitter release at the hippocampal-LS synapse, and regulates spike frequency and spike frequency adaptation in subpopulations of LS neurons. We further demonstrated that loss of TMEM16B function promotes lengthened displays of aggressive behaviors by male mice during the resident intruder paradigm. In conclusion, our findings suggest that TMEM16B function contributes to neuronal excitability in subpopulations of LS neurons and the regulation of aggression in male mice. Aggression is a behavior that arose evolutionarily from the necessity to compete for limited resources and survival. One particular brain region involved in aggression is the lateral septum (LS). In this study, we characterized the expression of the TMEM16B calcium-activated chloride channel in the LS and showed that TMEM16B regulates the action potential firing frequency of LS neurons. We discovered that loss of TMEM16B function lengthens the displays of aggressive behaviors in male mice. These findings suggest that TMEM16B plays an important role in regulating LS neuronal excitability and behaviors associated with LS function, thereby contributing to our understanding of how the LS may regulate aggression.
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http://dx.doi.org/10.1523/JNEUROSCI.3137-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733546PMC
September 2019

Metabolic Detection of Bruton's Tyrosine Kinase Inhibition in Mantle Cell Lymphoma Cells.

Mol Cancer Res 2019 06 12;17(6):1365-1377. Epub 2019 Mar 12.

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Current methods to evaluate effects of kinase inhibitors in cancer are suboptimal. Analysis of changes in cancer metabolism in response to the inhibitors creates an opportunity for better understanding of the interplay between cell signaling and metabolism and, from the translational perspective, potential early evaluation of response to the inhibitors as well as treatment optimization. We performed genomic, metabolomic, and fluxomic analyses to evaluate the mechanism of action of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (IBR) in mantle cell lymphoma (MCL) cells. Our comprehensive analysis of the data generated by these diverse technologies revealed that IBR profoundly affected key metabolic pathways in IBR-sensitive cells including glycolysis, pentose phosphate pathway, TCA cycle, and glutaminolysis while having much less effects on IBR-poorly responsive cells. Changes in H magnetic resonance spectroscopy (MRS)-detectable lactate and alanine concentrations emerged as promising biomarkers of response and resistance to IBR as demonstrated from experiments on various MCL cell lines. The metabolic network analysis on the C MRS and C LC/MS experimental data provided quantitative estimates of various intracellular fluxes and energy contributions. Glutaminolysis contributed over 50% of mitochondrial ATP production. Administration of the glutaminase inhibitor CB-839 induced growth suppression of the IBR-poorly responsive cells. IMPLICATIONS: Our study demonstrates application of the advanced metabolomic/fluxomic techniques for comprehensive, precise, and prompt evaluations of the effects of kinase inhibition in MCL cells and has strong translational implications by potentially permitting early evaluation of cancer patient response versus resistance to kinase inhibitors and on design of novel therapies for overcoming the resistance.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0256DOI Listing
June 2019

XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB.

Mol Cancer Ther 2018 12;17(12):2564-2574

Department of Pathology, University of Chicago, Chicago, Illinois.

Inhibition of B-cell receptor (BCR) signaling through the BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one third of patients do not respond well to the drug, and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib. We found that selinexor had a broader antitumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib remained sensitive to selinexor. We showed that selinexor induced apoptosis/cell-cycle arrest and XPO-1 knockdown also retarded cell growth. Furthermore, downregulation of the NFκB gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NFκB was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IκB that was accompanied by the reduction of DNA-binding activity of NFκB, suggesting that NFκB is trapped in an inhibitory complex. Coimmunoprecipitation confirmed that p65 of NFκB and IκB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IκB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NFκB pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NFκB inhibition.
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0789-ATRDOI Listing
December 2018

Activation of orexin system facilitates anesthesia emergence and pain control.

Proc Natl Acad Sci U S A 2018 11 22;115(45):E10740-E10747. Epub 2018 Oct 22.

Department of Physiology, University of California, San Francisco, CA 94158;

Orexin (also known as hypocretin) neurons in the hypothalamus play an essential role in sleep-wake control, feeding, reward, and energy homeostasis. The likelihood of anesthesia and sleep sharing common pathways notwithstanding, it is important to understand the processes underlying emergence from anesthesia. In this study, we investigated the role of the orexin system in anesthesia emergence, by specifically activating orexin neurons utilizing the designer receptors exclusively activated by designer drugs (DREADD) chemogenetic approach. With injection of adeno-associated virus into the orexin-Cre transgenic mouse brain, we expressed the DREADD receptor hM3Dq specifically in orexin neurons and applied the hM3Dq ligand clozapine to activate orexin neurons. We monitored orexin neuronal activities by c-Fos staining and whole-cell patch-clamp recording and examined the consequence of orexin neuronal activation via EEG recording. Our results revealed that the orexin-DREADD mice with activated orexin neurons emerged from anesthesia with significantly shorter latency than the control mice. As an indication of reduced pain sensitivity, these orexin-DREADD mice took longer to respond to the 55 °C thermal stimuli in the hot plate test and exhibited significantly less frequent licking of the formalin-injected paw in the formalin test. Our study suggests that approaches to activate the orexin system can be beneficial in postoperative recovery.
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http://dx.doi.org/10.1073/pnas.1808622115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233126PMC
November 2018

Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies.

Clin Cancer Res 2019 02 17;25(4):1174-1184. Epub 2018 Oct 17.

Biology, Portola Pharmaceuticals, Inc., South San Francisco, California.

Purpose: Preclinical studies suggest SYK and JAK contribute to tumor-intrinsic and microenvironment-derived survival signals. The pharmacodynamics of cerdulatinib, a dual SYK/JAK inhibitor, and associations with tumor response were investigated.

Patients And Methods: In a phase I dose-escalation study in adults with relapsed/refractory B-cell malignancies, cerdulatinib was administered orally to sequential dose-escalation cohorts using once-daily or twice-daily schedules. The study enrolled 8 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 13 with follicular lymphoma, 16 with diffuse large B-cell lymphoma (DLBCL), and 6 with mantle cell lymphoma. Correlation of tumor response with pharmacodynamic markers was determined in patients with meaningful clinical responses.

Results: Following cerdulatinib administration, complete SYK and JAK pathway inhibition was achieved in whole blood of patients at tolerated exposures. Target inhibition correlated with serum cerdulatinib concentration, and IC values against B-cell antigen receptor (BCR), IL2, IL4, and IL6 signaling pathways were 0.27 to 1.11 μmol/L, depending on the phosphorylation event. Significant correlations were observed between SYK and JAK pathway inhibition and tumor response. Serum inflammation markers were reduced by cerdulatinib, and several significantly correlated with tumor response. Diminished expression of CD69 and CD86 (B-cell activation markers), CD5 (negative regulator of BCR signaling), and enhanced expression of CXCR4 were observed in 2 patients with CLL, consistent with BCR and IL4 suppression and loss of proliferative capacity.

Conclusions: Cerdulatinib potently and selectively inhibited SYK/JAK signaling at tolerated exposures in patients with relapsed/refractory B-cell malignancies. The extent of target inhibition in whole-blood assays and suppression of inflammation correlated with tumor response. (ClinicalTrials.gov ID:NCT01994382).
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1047DOI Listing
February 2019

Chloroquine Restores Ganglioside Homeostasis and Improves Pathological and Behavioral Outcomes Post-stroke in the Rat.

Mol Neurobiol 2019 May 25;56(5):3552-3562. Epub 2018 Aug 25.

Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada.

Perturbations of ganglioside homeostasis have been observed following stroke whereby toxic simple gangliosides GM2 and GM3 accumulate, while protective complex species GM1 and GD1 are reduced. Thus, there is a need for therapeutic interventions which can prevent ganglioside dysregulation after stroke. A pharmacological intervention using chloroquine was selected for its transient lysosomotropic properties which disrupt the activity of catabolic ganglioside enzymes. Chloroquine was administered both in vitro (0.1 μM), to primary cortical neurons exposed to GM3 toxicity, and in vivo (45 mg/kg i.p.), to 3-month-old male Wistar rats that underwent a severe stroke injury. Chloroquine was administered for seven consecutive days beginning 3 days prior to the stroke injury. Gangliosides were examined using MALDI imaging mass spectrometry at 3 and 21 days after the injury, and motor deficits were examined using the ladder task. Chloroquine treatment prevented ganglioside dysregulation 3 days post-stroke and partially prevented complex ganglioside depletion 21 days post-stroke. Exogenous GM3 was found to be toxic to primary cortical neurons which was protected by chloroquine treatment. Motor deficits were prevented in the forelimbs of stroke-injured rats with chloroquine treatment and was associated with decreased inflammation, neurodegeneration, and an increase in cell survival at the site of injury. Chloroquine administration prevents ganglioside dysregulation acutely, protects against GM3 toxicity in neurons, and is associated with long-term functional and pathological improvements after stroke in the rat. Therefore, targeting lipid dysregulation using lysosomotropic agents such as chloroquine may represent a novel therapeutic avenue for stroke injuries.
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http://dx.doi.org/10.1007/s12035-018-1317-0DOI Listing
May 2019

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma.

Blood Adv 2018 08;2(16):2039-2051

Lymphoma Translational Pathology, Department of Pathology, University of Chicago, Chicago, IL.

The BTK inhibitor ibrutinib has demonstrated a remarkable therapeutic effect in mantle cell lymphoma (MCL). However, approximately one-third of patients do not respond to the drug initially. To identify the mechanisms underlying primary ibrutinib resistance in MCL, we analyzed the transcriptome changes in ibrutinib-sensitive and ibrutinib-resistant cell lines on ibrutinib treatment. We found that MYC gene signature was suppressed by ibrutinib in sensitive but not resistant cell lines. We demonstrated that MYC gene was structurally abnormal and MYC protein was overexpressed in MCL cells. Further, MYC knockdown with RNA interference inhibited cell growth in ibrutinib-sensitive as well as ibrutinib-resistant cells. We explored the possibility of inhibiting MYC through HSP90 inhibition. The chaperon protein is overexpressed in both cell lines and primary MCL cells from the patients. We demonstrated that MYC is a bona fide client of HSP90 in the context of MCL by both immunoprecipitation and chemical precipitation. Furthermore, inhibition of HSP90 using PU-H71 induced apoptosis and caused cell cycle arrest. PU-H71 also demonstrates strong and relatively specific inhibition of the MYC transcriptional program compared with other oncogenic pathways. In a MCL patient-derived xenograft model, the HSP90 inhibitor retards tumor growth and prolongs survival. Last, we showed that PU-H71 induced apoptosis and downregulated MYC protein in MCL cells derived from patients who were clinically resistant to ibrutinib. In conclusion, MYC activity underlies intrinsic resistance to ibrutinib in MCL. As a client protein of HSP90, MYC can be inhibited via PU-H71 to overcome primary ibrutinib resistance.
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http://dx.doi.org/10.1182/bloodadvances.2018016048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113611PMC
August 2018

System for Informatics in the Molecular Pathology Laboratory: An Open-Source End-to-End Solution for Next-Generation Sequencing Clinical Data Management.

J Mol Diagn 2018 07 24;20(4):522-532. Epub 2018 Apr 24.

Division of Genomic and Molecular Pathology, Department of Pathology, The University of Chicago, Chicago, Illinois; Informatics Subdivision Leadership, Association for Molecular Pathology, Bethesda, Maryland. Electronic address:

Next-generation sequencing (NGS) diagnostic assays increasingly are becoming the standard of care in oncology practice. As the scale of an NGS laboratory grows, management of these assays requires organizing large amounts of information, including patient data, laboratory processes, genomic data, as well as variant interpretation and reporting. Although several Laboratory Information Systems and/or Laboratory Information Management Systems are commercially available, they may not meet all of the needs of a given laboratory, in addition to being frequently cost-prohibitive. Herein, we present the System for Informatics in the Molecular Pathology Laboratory (SIMPL), a free and open-source Laboratory Information System/Laboratory Information Management System for academic and nonprofit molecular pathology NGS laboratories, developed at the Genomic and Molecular Pathology Division at the University of Chicago Medicine. SIMPL was designed as a modular end-to-end information system to handle all stages of the NGS laboratory workload from test order to reporting. We describe the features of SIMPL, its clinical validation at University of Chicago Medicine, and its installation and testing within a different academic center laboratory (University of Colorado), and we propose a platform for future community co-development and interlaboratory data sharing.
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http://dx.doi.org/10.1016/j.jmoldx.2018.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039793PMC
July 2018

Ultraviolet Radiation Inhibits Mammary Carcinogenesis in an ER-Negative Murine Model by a Mechanism Independent of Vitamin D.

Cancer Prev Res (Phila) 2018 07 10;11(7):383-392. Epub 2018 Apr 10.

Children's Hospital Oakland Research Institute, Oakland, California.

Three decades ago, the Garlands postulated that vitamin D produced in the skin by ultraviolet radiation (UVR)-induced conversion of 7-dehydrocholesterol to pre-D has anticancer effects, thus triggering more than 9,500 publications on D and cancer. Here, we report that UVR treatment of transgenic mice of the well-established C3(1)/SV40 Tag mammary cancer model significantly inhibits both autochthonous carcinogenesis and allograft tumor growth, but in contrast neither dietary nor topical D influences mammary carcinogenesis in this specific mouse model. Furthermore, UVR's inhibitory effects occur irrespective of whether or not the treatment increases circulating D in the mice. The inhibitory effect of UVR on autochthonous tumors occurs at or before the stage of ductal carcinoma in situ. Our studies indicate clearly that UVR can exert D-independent anticancer effects in C3(1)/SV40 Tag mice. Therefore, supplemental D may not mimic all possible beneficial effects of UVR, and uncovering non-D-mediated mechanisms of UVR tumor inhibition may lead to novel strategies for cancer prevention. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0195DOI Listing
July 2018

MYD88 Mutations and Sensitivity to Ibrutinib Therapy.

Authors:
Y Lynn Wang

J Mol Diagn 2018 03;20(2):264-266

Department of Pathology, University of Chicago, Chicago, Illinois. Electronic address:

This Correspondence relates to the article by Bobee et al (Determination of Molecular Subtypes of Diffuse Large B-Cell Lymphoma Using a Reverse Transcriptase Multiplex Ligation-Dependent Probe Amplification Classifier: A CALYM Study. J Mol Diagn 2017,19:892-904).
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http://dx.doi.org/10.1016/j.jmoldx.2017.11.006DOI Listing
March 2018

The Sixth Transmembrane Segment Is a Major Gating Component of the TMEM16A Calcium-Activated Chloride Channel.

Neuron 2018 03 22;97(5):1063-1077.e4. Epub 2018 Feb 22.

Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

Calcium-activated chloride channels (CaCCs) formed by TMEM16A or TMEM16B are broadly expressed in the nervous system, smooth muscles, exocrine glands, and other tissues. With two calcium-binding sites and a pore within each monomer, the dimeric CaCC exhibits voltage-dependent calcium sensitivity. Channel activity also depends on the identity of permeant anions. To understand how CaCC regulates neuronal signaling and how CaCC is, in turn, modulated by neuronal activity, we examined the molecular basis of CaCC gating. Here, we report that voltage modulation of TMEM16A-CaCC involves voltage-dependent occupancy of calcium- and anion-binding site(s) within the membrane electric field as well as a voltage-dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment.
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http://dx.doi.org/10.1016/j.neuron.2018.01.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860880PMC
March 2018

Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL.

Blood Adv 2017 May 2;1(12):715-727. Epub 2017 May 2.

Department of Pathology.

Ibrutinib has generated remarkable responses in patients with chronic lymphocytic leukemia (CLL), including those with an unfavorable cytogenetic profile. However, patients develop resistance, with poor outcomes and no established treatment options. Mutations in and have emerged as main mechanisms of drug resistance, but not all patients carry these mutations. Further understanding of mechanisms of resistance is urgently needed and will support rational development of new therapeutic strategies. To that end, we characterized the genomic profiles of serial samples from 9 patients with ibrutinib-relapsed disease, including 6 who had Richter transformation. Mutations, indels, copy-number aberrations, and loss of heterozygosity were assessed using next-generation sequencing and single-nucleotide polymorphism array. We found that 18p deletion (del(18p)), together with del(17p)/ mutations, was present in 5 of 9 patients before ibrutinib therapy. In addition to , we identified , a structurally novel mutation located in the SH2 domain of BTK. Minor clones with low allele frequencies were captured in addition to major clones. Although loss predisposes patients for relapse, clone size of loss may diminish during disease progression while mutant clone expands. In patients who had Richter transformation, we found that the transformed cells were clonal descendants of circulating leukemia cells but continued to undergo evolution and drifts. Surprisingly, transformed lymphoma cells in tissue may acquire a different mutation from that in the CLL leukemia cells. Collectively, these results provide insights into clonal evolution underlying ibrutinib relapse and prompt further investigation on genomic abnormalities that have clinical application potential.
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http://dx.doi.org/10.1182/bloodadvances.2016003632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728051PMC
May 2017

B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy.

Clin Cancer Res 2017 Aug 27;23(15):4212-4223. Epub 2017 Mar 27.

Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma patient-derived xenograft (PDX) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options. We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice. We subjected the PDX models to histopathologic and phenotypical examination, sequencing, and drug efficacy analysis. Primary and acquired resistance to ibrutinib, an oral covalent inhibitor of Bruton tyrosine kinase, were investigated to elucidate the mechanisms underlying ibrutinib resistance and to identify drug treatments to overcome resistance. The PDXs maintained the same biological, histopathologic, and immunophenotypical features, retained similar genetic mutations, and produced comparable drug responses with the original patient tumors. In the acquired ibrutinib-resistant PDXs, PLC-γ2, p65, and Src were downregulated; however, a PI3K signaling pathway member was upregulated. Inactivation of the PI3K pathway with the inhibitor idelalisib in combination with ibrutinib significantly inhibited the growth of the ibrutinib-resistant tumors. Furthermore, we used a PDX model derived from a clinically ibrutinib-relapsed patient to evaluate various therapeutic choices, ultimately eliminating the tumor cells in the patient's peripheral blood. Our results demonstrate that the B-cell lymphoma PDX model is an effective system to predict and personalize therapies and address therapeutic resistance in B-cell lymphoma patients. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540787PMC
August 2017

Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment.

Oncotarget 2017 Feb;8(8):12953-12967

Department of Pathology, Lymphoma Translational Pathology, University of Chicago, Chicago, IL, USA.

Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases. We demonstrated that cerdulatinib delivered potent tumor inhibition in 60 primary CLL patient samples, especially in those with poor prognostic indicators. Importantly, cerdulatinib, but not ibrutinib, is able to overcome the support of microenvironment and induces CLL cell death at clinically achievable concentrations. Notably, cerdulatinib blocked proliferation of ibrutinib-resistant primary CLL cells and of BTKC481S-transfected/ibrutinib-resistant lymphoma cells. These anti-tumor effects are well correlated with the inhibition of BCR and JAK-STAT signaling and downstream inhibition of the functions of AKT, ERK and NFκB. Collectively, our results show that simultaneous targeting of BCR and JAK-STAT pathways is a more effective strategy relative to single BTK inhibition.
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http://dx.doi.org/10.18632/oncotarget.14588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355069PMC
February 2017

Clinical Validation of a Next-Generation Sequencing Genomic Oncology Panel via Cross-Platform Benchmarking against Established Amplicon Sequencing Assays.

J Mol Diagn 2017 01 9;19(1):43-56. Epub 2016 Nov 9.

Division of Genomic and Molecular Pathology, The University of Chicago, Chicago, Illinois. Electronic address:

Next-generation sequencing (NGS) genomic oncology profiling assays have emerged as key drivers of personalized cancer care and translational research. However, validation of these assays to meet strict clinical standards has been historically problematic because of both significant assay complexity and a scarcity of optimal validation samples. Herein, we present the clinical validation of 76 genes from a novel 1212-gene large-scale hybrid capture cancer sequencing assay (University of Chicago Medicine OncoPlus) using full-data comparisons against multiple clinical NGS amplicon-based assays to yield dramatic increases in per-sample data comparison efficiency compared with previously published validations. Using a sample set of 104 normal, solid tumor, and hematopoietic malignancy specimens, head-to-head NGS data analyses allowed for 6.8 million individual clinical base call comparisons, including 2729 previously confirmed variants, with 100% sensitivity and specificity. University of Chicago Medicine OncoPlus showed excellent performance for detection of single-nucleotide variants, insertions/deletions up to 52 bp, and FLT3 internal tandem duplications of up to 102 bp or larger. Highly concordant copy number variant and ALK/RET/ROS1 gene fusion detection were also observed. In addition to underlining the efficiency of NGS validation via full-data benchmarking against existing clinical NGS assays, this study also highlights the degree of performance similarity between hybrid capture and amplicon assays that is attainable with the application of strict quality control parameters and optimized computational analytics.
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http://dx.doi.org/10.1016/j.jmoldx.2016.07.012DOI Listing
January 2017

Increased Expression of GM1 Detected by Electrospray Mass Spectrometry in Rat Primary Embryonic Cortical Neurons Exposed to Glutamate Toxicity.

Anal Chem 2016 08 18;88(15):7844-52. Epub 2016 Jul 18.

Department of Clinical Neurological Sciences, London Health Sciences Centre, University of Western Ontario , London, Ontario N6A 5A5, Canada.

Neurons within different brain regions have varying levels of vulnerability to external stress and respond differently to injury. A potential reason to explain this may lie within a key lipid class of the cell's plasma membrane called gangliosides. These glycosphingolipid species have been shown to play various roles in the maintenance of neuronal viability. The purpose of this study is to use electrospray ionization mass spectrometry (ESI-MS) and immunohistochemistry to evaluate the temporal expression profiles of gangliosides during the course of neurodegeneration in rat primary cortical neurons exposed to glutamate toxicity. Primary embryonic (E18) rat cortical neurons were cultured to DIV (days in vitro) 14. Glutamate toxicity was induced for 1, 3, 6, and 24 h to injure and kill neurons. Immunofluorescence was used to stain for GM1 and GM3 species, and ESI-MS was used to quantify the ganglioside species expressed within these injured neurons. ESI-MS data revealed that GM1, GM2, and GM3 were up-regulated in neurons exposed to glutamate. Interestingly, using immunofluorescence, we demonstrated that the GM1 increase following glutamate exposure occurred in viable neurons, possibly indicating a potential intrinsic neuroprotective response. To test this potential neuroprotective property, neurons were pretreated with GM1 for 24 h prior to glutamate exposure. Pretreatment with GM1 conferred significant neuroprotection against glutamate-induced cell death. Overall, work from this study validates the use of ESI-MS for cell-derived gangliosides and supports the further development of lipid based strategies to protect against neuron cell death.
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http://dx.doi.org/10.1021/acs.analchem.6b01940DOI Listing
August 2016

Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib.

Oncotarget 2016 Jan;7(4):4598-610

Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago, Chicago, IL, USA.

In chronic lymphocytic leukemia (CLL), patients with unmutated immunoglobulin heavy chain variable region gene (UM-CLL) have worse outcomes than mutated CLL (M-CLL) following chemotherapy or chemoimmunotherapy. However, in the era of BCR-targeted therapies, the adverse prognostic impact of unmutated IGHV seems to be diminishing, and there are clinical datasets showing unexpected improved responses in UM-CLL. We investigated the biological differences of BTK activity between these subgroups and further compared the impact of ibrutinib on molecular and cellular behaviors. Immunoblotting analysis revealed that phosphorylated active BTK is significantly higher in UM-CLL. Moreover, UM-CLL, compared to M-CLL, displayed a much higher proliferative capacity that was correlated with higher phospho-BTK and greater sensitivity to ibrutinib. In addition, BTK depletion with siRNA led to a more prominent reduction in the proliferation of UM-CLL, suggesting that elevated BTK activity is responsible for increased cell proliferation. Further, cell signaling activity by multiple measurements was consistently higher in UM-CLL accompanied by a higher sensitivity to ibrutinib. These studies link UM-CLL to elevated BCR signaling, heightened BTK-dependent cell proliferation and increased sensitivity to ibrutinib. The prognostic significance of IGHV mutation should be reevaluated in the era of new therapies targeting BCR signaling.
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http://dx.doi.org/10.18632/oncotarget.6727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826229PMC
January 2016

Impaired SNX9 Expression in Immune Cells during Chronic Inflammation: Prognostic and Diagnostic Implications.

J Immunol 2016 Jan 25;196(1):156-67. Epub 2015 Nov 25.

Lautenberg Center for General and Tumor Immunology, Israel-Canada Medical Research Institute, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel; and

Chronic inflammation is associated with immunosuppression and downregulated expression of the TCR CD247. In searching for new biomarkers that could validate the impaired host immune status under chronic inflammatory conditions, we discovered that sorting nexin 9 (SNX9), a protein that participates in early stages of clathrin-mediated endocytosis, is downregulated as well under such conditions. SNX9 expression was affected earlier than CD247 by the generated harmful environment, suggesting that it is a potential marker sensing the generated immunosuppressive condition. We found that myeloid-derived suppressor cells, which are elevated in the course of chronic inflammation, are responsible for the observed SNX9 reduced expression. Moreover, SNX9 downregulation is reversible, as its expression levels return to normal and immune functions are restored when the inflammatory response and/or myeloid-derived suppressor cells are neutralized. SNX9 downregulation was detected in numerous mouse models for pathologies characterized by chronic inflammation such as chronic infection (Leishmania donovani), cancer (melanoma and colorectal carcinoma), and an autoimmune disease (rheumatoid arthritis). Interestingly, reduced levels of SNX9 were also observed in blood samples from colorectal cancer patients, emphasizing the feasibility of its use as a diagnostic and prognostic biomarker sensing the host's immune status and inflammatory stage. Our new discovery of SNX9 as being regulated by chronic inflammation and its association with immunosuppression, in addition to the CD247 regulation under such conditions, show the global impact of chronic inflammation and the generated immune environment on different cellular pathways in a diverse spectrum of diseases.
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http://dx.doi.org/10.4049/jimmunol.1402877DOI Listing
January 2016

Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma.

Oncotarget 2015 Dec;6(41):43881-96

Department of Pathology, Division of Genomic and Molecular Pathology, University of Chicago, Chicago, IL, USA.

B-cell receptor (BCR) and JAK/STAT pathways play critical roles in diffuse large B-cell lymphoma (DLBCL). Herein, we investigated the anti-lymphoma activity of cerdulatinib, a novel compound that dually targets SYK and JAK/STAT pathways. On a tissue microarray of 62 primary DLBCL tumors, 58% expressed either phosphorylated SYK or STAT3 or both. SYK and STAT3 are also phosphorylated in a panel of eleven DLBCL cell lines although ABC and GCB subtypes exhibited different JAK/STAT and BCR signaling profiles. In both ABC and GCB cell lines, cerdulatinib induced apoptosis that was associated with caspase-3 and PARP cleavage. The compound also blocked G1/S transition and caused cell cycle arrest, accompanied by inhibition of RB phosphorylation and down-regulation of cyclin E. Phosphorylation of BCR components and STAT3 was sensitive to cerdulatinib in both ABC and GCB cell lines under stimulated conditions. Importantly, JAK/STAT and BCR signaling can be blocked by cerdulatinib in primary GCB and non-GCB DLBCL tumor cells that were accompanied by cell death. Our work provides mechanistic insights into the actions of cerdulatinib, suggesting that the drug has a broad anti-tumor activity in both ABC and GCB DLBCL, at least in part by inhibiting SYK and JAK pathways.
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http://dx.doi.org/10.18632/oncotarget.6316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791274PMC
December 2015

Female Sexual Health Training for Oncology Providers: New Applications.

Sex Med 2015 Sep 14;3(3):189-97. Epub 2015 Apr 14.

Lankenau Institute for Medical Research, Lankenau Medical Center Wynnewood, PA, USA ; Department of Oncology Programs, Lankenau Medical Center Wynnewood, PA, USA.

Introduction: Sexual health care remains an unmet need for women with cancer. Many barriers are described, such as provider discomfort and lack of training; however, there is little evidence-based guidance regarding how to effectively address these obstacles.

Aim: This pilot study was performed to determine whether brief, targeted sexual health training for oncology providers results in improved provider comfort level and frequency of addressing female cancer-related sexual issues.

Methods: A brief (30-45 minute), targeted sexual health training program focused on improving comfort level, knowledge and communication skills when addressing breast cancer-related sexual issues was developed by the primary author. Using a pretest-posttest format, this educational program was provided to oncology providers (physicians and nurses/other allied health) from a suburban health-care system. Surveys based on 5-point Likert scales were provided before and 3-6 month post training.

Main Outcome Measures: Primary endpoints were changes in mean Likert scores for provider comfort level and self-reported frequency of addressing sexual issues. A secondary endpoint was change in mean Likert scores for perception of access to sexual health resources/referrals.

Results: Eligible respondents included 8 oncologists, 4 surgeons, and 62 nurses/other allied health. For total respondents, comparison of mean Likert scores for survey 1 (n = 71) and survey 2 (n = 36) demonstrated statistically significant increases for all parameters queried, including provider comfort level with bringing up (Pre mean Likert score = 3.4, Post = 4.3, P < 0.0001) and coordinating care (Pre = 3.5, Post = 4.6, P < 0.0001), and frequency of addressing sexual issues for both diagnosis/treatment and surveillance phase (Pre = 2.4, Post = 3.3, P ≤ 0.0052).

Conclusion: Brief, targeted sexual health training for oncology providers positively correlated with improved provider comfort level and frequency of addressing female cancer-related sexual issues.
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http://dx.doi.org/10.1002/sm2.66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599556PMC
September 2015

Prognosis in Chronic Lymphocytic Leukemia-Reply.

JAMA Oncol 2015 Oct;1(7):988-9

Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1001/jamaoncol.2015.2532DOI Listing
October 2015

Differential Gene Expression Profiling of Orbital Adipose Tissue in Thyroid Orbitopathy.

Invest Ophthalmol Vis Sci 2015 Oct;56(11):6438-47

Department of Ophthalmology, Flinders University, Bedford Park, South Australia, Australia.

Purpose: We aimed to determine differentially expressed genes relevant to orbital inflammation and orbital fat expansion in thyroid orbitopathy (TO) using microarray gene profiling in a case-control study.

Methods: Human orbital adipose samples were obtained from individuals with active TO (n = 12), inactive TO (n = 21), and normal controls (n = 21). Gene expression profiles were examined using microarray analysis and were compared between active and inactive TO, and between active TO and normal controls. Top ranked differentially expressed genes were validated by real-time RT-PCR in an additional eight active TO, 13 inactive TO, and 11 normal controls and correlated with gene set enrichment analysis (GSEA) and molecular pathways analysis.

Results: Seven hundred twenty-one probes (683 genes) and 806 probes (735 genes) were significantly differentially expressed in comparing active to inactive TO and in comparing active TO to healthy controls, respectively. All selected genes were confirmed to be differentially expressed by real-time RT-PCR. Multiple top ranked genes in active versus inactive TO comparison are overrepresented by immune and inflammatory response genes. They include defensins (DEFA1, DEFA1B, DEFA3), which were overexpressed by 3.05- to 4.14-fold and TIMD4 by 4.20-fold. Markers for adipogenesis were overexpressed including SCD, FADS1, and SCDP1. Gene set enrichment analysis revealed dysregulation of epigenetic signatures, T-cell activation, Th1 differentiation, defensin pathway, cell adhesion, cytoskeleton organization, apoptosis, cell cycling, and lipid metabolism in active TO.

Conclusions: Active TO is characterized by upregulation of genes involved in cell-mediated immune, innate immune, and inflammatory response and enhanced orbital adipogenesis. TIMD4, DEFA1, DEFA1B, and DEFA3 genes may be involved in the innate immune-mediated orbital inflammation in TO. Epigenetic mechanisms may play a role in the pathogenesis of TO.
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http://dx.doi.org/10.1167/iovs.15-17185DOI Listing
October 2015

Amplicon Indel Hunter Is a Novel Bioinformatics Tool to Detect Large Somatic Insertion/Deletion Mutations in Amplicon-Based Next-Generation Sequencing Data.

J Mol Diagn 2015 Nov 28;17(6):635-43. Epub 2015 Aug 28.

Division of Genomic and Molecular Pathology, Department of Pathology, The University of Chicago, Chicago, Illinois. Electronic address:

Amplicon-based targeted next-generation sequencing assays are used widely to test for clinically relevant somatic mutations in cancer. However, accurate detection of large insertions and deletions (indels) via these assays remains challenging. Sequencing reads that cover these anomalies are, by definition, different from the reference sequence, and lead to variable performance of alignment algorithms. Reads with large indels may be aligned incorrectly, causing incorrect calls, or may remain unmapped and essentially ignored by downstream informatics pipeline sub-processes. Herein, we describe Amplicon Indel Hunter (AIH), a novel large (>5-bp) indel detection method that is reference genome independent and highly sensitive for the identification of somatic indels in amplicon-based, paired-end, next-generation sequencing data. We validated the algorithm for sensitivity and specificity using a set of clinical cancer samples with Clinical Laboratory Improvement Amendment-confirmed indels as well as in silico mutated data sets. The AIH detected 100% of tested large indels with relatively higher mutant allele frequencies compared with a variety of traditional aligners, which showed variably reduced sensitivity and specificity by comparison. The AIH especially outperformed alignment-based methods for detection of all tested FLT3 internal tandem duplications up to 102 bp. Because AIH runs in parallel to traditional alignment-based informatics pathways, it can be readily incorporated into nearly any analysis pipeline for somatic mutation detection in paired-end amplicon-based data.
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http://dx.doi.org/10.1016/j.jmoldx.2015.06.005DOI Listing
November 2015

Predicting Prognosis in Chronic Lymphocytic Leukemia in the Contemporary Era.

JAMA Oncol 2015 Oct;1(7):965-74

Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago, Chicago, Illinois.

Importance: Next-generation sequencing has identified new genetic markers that have altered prognosis for patients with chronic lymphocytic leukemia (CLL) at diagnosis. Understanding the significance of these prognostic indicators and recognizing their potential impact on treatment selection and patients' outcomes is critical for clinicians and investigators.

Objective: To review novel prognostic factors at CLL diagnosis that have shown an impact on the prognosis and outcomes of this disease.

Evidence Review: Literature from January 2004 through December 2014 was searched in PubMed, Cochrane Central Register of Controlled Trials, and Scopus to identify English-language, peer-reviewed articles on clinical and prognostic factors for CLL (TP53, ATM, NOTCH1, SF3B1, BIRC3, and MYD88). Reference lists were subsequently reviewed for additional articles. A total of 450 articles was identified, and 48 articles meeting inclusion criteria were reviewed.

Findings: Among prognostic markers reviewed, chromosomal aberrations have been validated and are currently used clinically to predict prognosis. Patients with 17p13.1 deletion have poor response to chemoimmunotherapy and are treated differently, with some undergoing allogeneic transplantation in first remission. CD38 and ZAP-70 status of malignant cells and unmutated immunoglobulin variable heavy chain gene have similarly been validated to predict adverse prognosis, but their implications on treatment selection have not been proven. The presence of TP53 and ATM mutations predicts worse prognosis, which has been corroborated in various studies. Patients with TP53 mutations have lower responses to chemoimmunotherapy. Furthermore, patients with TP53 and ATM mutations have inferior progression-free survival and overall survival, independent of other factors. Patients carrying the NOTCH1 and SF3B1 mutations have worse prognosis; patients with the NOTCH1 mutation have lower response rates to standard chemoimmunotherapy. The impact of BIRC3 on prognosis and survival requires further confirmation.

Conclusions And Relevance: The heterogeneous clinical course of CLL is likely explained by underlying molecular prognostic factors. Moving forward, analyzing these factors at diagnosis is recommended for better prognostication.
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http://dx.doi.org/10.1001/jamaoncol.2015.0779DOI Listing
October 2015

Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma.

Br J Haematol 2015 Aug 9;170(4):445-56. Epub 2015 Apr 9.

Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago, Chicago, IL, USA.

Bruton tyrosine kinase (BTK), a mediator of B-cell receptor (BCR) signalling, has been implicated in the pathogenesis of chronic lymphocytic leukaemia (CLL) and other B-cell malignancies. Ibrutinib is an orally bioavailable and highly specific BTK inhibitor that was recently approved for treatment of patients with recurrent CLL and mantle cell lymphoma (MCL). In addition, ibrutinib has shown efficacy in subsets of patients with diffuse large B cell lymphoma (DLBCL) and Waldenstrom macroglobulinaemia (WM). However, despite ibrutinib's activity in multiple B-cell malignancies, cases of primary and secondary resistance have emerged. The overall reported frequency of resistance is low, but follow-up in many trials was short, and we predict that the incidence of observed resistance will increase as clinical use outside clinical trials expands over time. Mutations within BTK have been described and clearly interfere with drug binding; however, there are also emerging alternative mechanisms that bypass BTK entirely and offer new opportunities for other targeted agents. Improved understanding of mechanisms of primary and secondary resistance is essential to developing appropriate therapeutic strategies to both prevent and address resistance. This review provides a comprehensive analysis of ibrutinib resistance in CLL, MCL, DLBCL and WM and considers potential strategies for further study.
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http://dx.doi.org/10.1111/bjh.13427DOI Listing
August 2015