Publications by authors named "Laura Z Rassenti"

82 Publications

Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans.

Leukemia 2021 Jul 20. Epub 2021 Jul 20.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.
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http://dx.doi.org/10.1038/s41375-021-01344-9DOI Listing
July 2021

Longitudinal single-cell dynamics of chromatin accessibility and mitochondrial mutations in chronic lymphocytic leukemia mirror disease history.

Cancer Discov 2021 Jun 10. Epub 2021 Jun 10.

Department of Medical Oncology, Dana-Farber Cancer Institute

While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure indicating clonal persistence, but dramatic changes following tight bottlenecks including disease transformation and relapse post-therapy, paralleled by acquisition of copy number variants, changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin states, providing insight into non-genetic sources of relapse. mtDNA mutations thus mirror disease history and provide naturally-occurring genetic barcodes to enable patient-specific study of cancer subclonal dynamics.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0276DOI Listing
June 2021

A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation.

Cancer Cell 2021 03;39(3):380-393.e8

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address:

Hotspot mutation of IKZF3 (IKZF3-L162R) has been identified as a putative driver of chronic lymphocytic leukemia (CLL), but its function remains unknown. Here, we demonstrate its driving role in CLL through a B cell-restricted conditional knockin mouse model. Mutant Ikzf3 alters DNA binding specificity and target selection, leading to hyperactivation of B cell receptor (BCR) signaling, overexpression of nuclear factor κB (NF-κB) target genes, and development of CLL-like disease in elderly mice with a penetrance of ~40%. Human CLL carrying either IKZF3 mutation or high IKZF3 expression was associated with overexpression of BCR/NF-κB pathway members and reduced sensitivity to BCR signaling inhibition by ibrutinib. Our results thus highlight IKZF3 oncogenic function in CLL via transcriptional dysregulation and demonstrate that this pro-survival function can be achieved by either somatic mutation or overexpression of this CLL driver. This emphasizes the need for combinatorial approaches to overcome IKZF3-mediated BCR inhibitor resistance.
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http://dx.doi.org/10.1016/j.ccell.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034546PMC
March 2021

miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors.

Blood 2021 May;137(18):2481-2494

Central European Institute of Technology, Masaryk University, Brno, Czech Republic.

B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NF-κB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by BCR activity.
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http://dx.doi.org/10.1182/blood.2020005627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610744PMC
May 2021

Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism.

Leukemia 2021 06 23;35(6):1621-1630. Epub 2020 Oct 23.

Center for Novel Therapeutics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.

Patients with chronic lymphocytic leukemia (CLL) have high plasma-levels of Wnt5a, which can induce phosphorylation of ERK1/2 and enhance CLL-cell proliferation. Such effects could be inhibited by treatment with an ERK1/2 inhibitor, ERK1/2-specific siRNA, or cirmtuzumab, an anti-ROR1 mAb. The CLL-derived line, MEC1, expresses Wnt5a, but not ROR1. MEC1 cells transfected to express ROR1 (MEC1-ROR1) had higher levels of phosphorylated ERK1/2 than parental MEC1, or MEC1 transfected with ROR1ΔPRD, a truncated ROR1 lacking the cytoplasmic proline-rich domain (PRD), or ROR1 a mutant ROR1 with a P→A substitution at 808, which is required for complexing with the Rac-specific-guanine-nucleotide-exchange factor DOCK2 upon stimulation with Wnt5a. We silenced DOCK2 with siRNA and found this repressed the capacity of Wnt5a to induce ERK1/2 phosphorylation in MEC1-ROR1 or CLL cells. CLL cells that expressed ROR1 had higher levels of phosphorylated ERK1/2 or DOCK2 than CLL cells lacking ROR1. Although we found ibrutinib could inhibit the phosphorylation of ERK1/2 and DOCK2 induced by B-cell-receptor ligation, we found that this drug was unable to inhibit Wnt5a-induced, ROR1-dependent phosphorylation of ERK1/2 or DOCK2. This study demonstrates that Wnt5a can induce activation of ERK1/2 and enhance CLL-cell proliferation via a ROR1/DOCK2-dependent pathway independent of BTK.
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http://dx.doi.org/10.1038/s41375-020-01055-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062590PMC
June 2021

Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to the graft-versus-leukemia effect.

Sci Transl Med 2020 09;12(561)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Leukemic relapse remains a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis for relapse of advanced lymphoid malignancies remains incompletely understood and may involve escape from the graft-versus-leukemia (GvL) effect. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features influence transplant outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic, and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post-HSCT relapse are shaped by distinct molecular dynamics. Early relapses after allo-HSCT exhibited notable genetic stability; single CLL cell transcriptional analysis demonstrated a cellular heterogeneity that was static over time. In contrast, CLL cells relapsing late after allo-HSCT displayed notable genetic evolution and evidence of neoantigen depletion, consistent with marked single-cell transcriptional shifts that were unique to each patient. We observed a greater rate of epigenetic change for late relapses not seen in early relapses or relapses after chemotherapy alone, suggesting that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for human leukocyte antigen (HLA) loss was observed, even when present in pretransplant subpopulations. Gain of stem cell modules was a common signature associated with leukemia relapse regardless of posttransplant relapse kinetics. These data elucidate the biological pathways that underlie GvL resistance and posttransplant relapse.
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http://dx.doi.org/10.1126/scitranslmed.abb7661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829680PMC
September 2020

NF-κB-p62-NRF2 survival signaling is associated with high ROR1 expression in chronic lymphocytic leukemia.

Cell Death Differ 2020 07 28;27(7):2206-2216. Epub 2020 Jan 28.

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.

Progression of chronic lymphocytic leukemia (CLL) and resistance to therapy are affected by tumor microenvironmental factors. One such factor is B-cell activating factor (BAFF), a cytokine that is produced mainly by nurse-like cells (NLC) and enhances CLL cells survival and modulates response to therapy. In CLL cells, BAFF activates NF-κB signaling, but how NF-κB supports CLL survival is not entirely clear. In this study we show that BAFF induces accumulation of the signaling and autophagy adaptor p62/SQSTM1 in a manner dependent on NF-κB activation. p62 potentiates mTORC1 signaling and activates NRF2, the master regulator of the anti-oxidant response. We found that expression of NRF2 target genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1), is particularly enriched in CLL cells with high ROR1 surface expression (ROR1). ROR1 CLL cells with elevated NQO1 expression exhibit resistance to drugs that induce ROS accumulation, such venetoclax. However, such cells are more sensitive to compound 29h, a pro-drug that only becomes active after being metabolized by NQO1. Accordingly, 29h sensitizes high NQO1 CLL cells to venetoclax. Collectively, our study unravels a previously unknown signaling network through which the NF-κB-p62-NRF2 axis protects ROR1-high CLL cells from ROS-inducing therapeutics.
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http://dx.doi.org/10.1038/s41418-020-0496-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308363PMC
July 2020

Genetic dynamics in untreated CLL patients with either stable or progressive disease: a longitudinal study.

J Hematol Oncol 2019 11 19;12(1):114. Epub 2019 Nov 19.

Unit of General Pathology, Center for Advanced Studies and Technology (CAST), University G. d'Annunzio Chieti-Pescara, Chieti, Italy.

Clonal evolution of chronic lymphocytic leukemia (CLL) often follows chemotherapy and is associated with adverse outcome, but also occurs in untreated patients, in which case its predictive role is debated. We investigated whether the selection and expansion of CLL clone(s) precede an aggressive disease shift. We found that clonal evolution occurs in all CLL patients, irrespective of the clinical outcome, but is faster during disease progression. In particular, changes in the frequency of nucleotide variants (NVs) in specific CLL-related genes may represent an indicator of poor clinical outcome.
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http://dx.doi.org/10.1186/s13045-019-0802-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862808PMC
November 2019

Dysregulation of different classes of tRNA fragments in chronic lymphocytic leukemia.

Proc Natl Acad Sci U S A 2019 11 13;116(48):24252-24258. Epub 2019 Nov 13.

Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210;

Chronic lymphocytic leukemia (CLL) is the most common human leukemia, and dysregulation of tRNA-derived short noncoding RNA (tsRNA) (tRF-1) expression is an accompanying event in the development of this disease. tsRNAs are fragments originating from the 3' end of tRNA precursors and do not contain mature tRNA sequences. In contrast to tsRNAs, mature tRFs (tRF-3s, tRF-5s, and internal tRFs) are produced from mature tRNA sequences and are redundant fragments. We investigated tsRNA expression in CLL and determined tsRNA signatures in indolent CLL and aggressive CLL vs. normal B cells. We noticed that both and are derived from distinct genes of pre-tRNA, and are down-regulated in CLL 3- to 5-fold vs. normal B cells. Thus, we investigated expression levels of tRF-5 fragments from tRNA in CLL samples and healthy controls, and determined that such fragments are down-regulated by 5-fold in CLLs vs. normal controls. Given these results, we investigated the expression of all mature tRFs in CLLs vs. normal controls. We found a drastic dysregulation of the expression of mature tRFs in CLL. In aggressive CLL, for the top 15 up-regulated fragments, linear fold change varied from 2,053- to 622-fold. For the top 15 down-regulated fragments in CLL, linear fold change varied from 314- to 52-fold. In addition, 964 mature tRFs were up-regulated at least 2-fold in CLL, while 701 fragments were down-regulated at least 2-fold. Similar results were obtained for indolent CLL. Our results suggest that mature tRFs may have oncogenic and/or tumor suppressor function in CLL.
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http://dx.doi.org/10.1073/pnas.1913695116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883801PMC
November 2019

Plasma B-Cell Maturation Antigen Levels are Elevated and Correlate with Disease Activity in Patients with Chronic Lymphocytic Leukemia.

Target Oncol 2019 10;14(5):551-561

Institute for Myeloma and Bone Cancer Research, 9201 Sunset Boulevard, Suite 300, West Hollywood, CA, 90069, USA.

Background: Chronic lymphocytic leukemia (CLL) is a malignancy of late B cells. In another late B-cell malignancy (multiple myeloma), levels of solubilized B-cell maturation antigen (sBCMA) are elevated and predict outcomes.

Objective: We sought to evaluate sBCMA as a possible prognostic factor and monitoring tool for patients with CLL.

Patients And Methods: Using an enzyme-linked immunosorbent assay (ELISA), we assessed plasma (p) levels of BCMA in 171 CLL patients and compared them with levels in healthy individuals.

Results: pBCMA levels were significantly higher among patients with CLL than those from healthy donors (p < 0.0001). Among patients with aggressive disease, pBCMA was elevated compared with patients with indolent disease (p < 0.001). Those with an initial pBCMA level in the highest quartile had a shorter time to first treatment compared with CLL patients with pBCMA levels in the lowest three quartiles (p < 0.0001). Among those in the highest quartile (pBCMA > 110.9 ng/mL), overall survival was shorter than those in the lowest three quartiles (p = 0.0007). Finally, among those patients who underwent serial pBCMA testing, changes in these levels correlated with changes in their clinical status.

Conclusions: Together, our findings show that pBCMA is a promising new prognostic and predictive indicator for patients with CLL.
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http://dx.doi.org/10.1007/s11523-019-00666-0DOI Listing
October 2019

Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-κB to repress autocrine STAT3 activation in chronic lymphocytic leukemia.

Blood 2019 09 13;134(13):1084-1094. Epub 2019 Aug 13.

Moores Cancer Center, University of California, San Diego, La Jolla, CA.

Coculture of nurse-like cells (NLCs) with chronic lymphocytic leukemia (CLL) cells induced leukemia cell phosphorylation of STAT3 (pSTAT3), which could be blocked by anti-Wnt5a antibodies or the anti-ROR1 monoclonal antibody, cirmtuzumab. Time-course studies revealed Wnt5a could induce activation of NF-κB within 30 minutes, but required more than 3 hours to induce pSTAT3. Culture of isolated CLL cells for 24 hours revealed Wnt5a-induced expression of interleukin 6 (IL-6), IL-8, CCL2, CCL3, CCL4, and CXCL1, which in turn could induce pSTAT3 in unstimulated CLL cells within 30 minutes. We found that Wnt5a could induce CLL cell expression of NF-κB target genes, including IL-6, and that this effect could be blocked by cirmtuzumab or drugs that inhibit NF-κB. Examination of CLL cells and plasma collected from patients treated with cirmtuzumab revealed reduced levels of phosphorylated p65 and diminished expression of NF-κB and STAT3 target genes in CLL cells, as well as lower plasma levels of IL-6, in the samples after therapy. Collectively, these studies indicate that Wnt5a/ROR1-dependent signaling contributes to CLL cell activation of NF-κB, which in turn causes autocrine IL-6-induced activation of pSTAT3. As such, this study demonstrates that cirmtuzumab can inhibit leukemia cell activation of both NF-κB and STAT3 in patients with CLL.
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http://dx.doi.org/10.1182/blood.2019001366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764264PMC
September 2019

Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia.

Blood 2019 08 10;134(8):688-698. Epub 2019 Jul 10.

Division of Hematology, Department of Internal Medicine, and.

Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.
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http://dx.doi.org/10.1182/blood.2019000490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706807PMC
August 2019

HNRNPL Restrains Targeting of BUB1 to Stabilize Aberrant Karyotypes of Transformed Cells in Chronic Lymphocytic Leukemia.

Cancers (Basel) 2019 Apr 23;11(4). Epub 2019 Apr 23.

Ageing Research Center and Translational medicine-CeSI-MeT, 66100 Chieti, Italy.

Aneuploidy and overexpression of () characterize most solid and hematological malignancies. We recently demonstrated that sustains aneuploidy at early stages of in vitro cellular transformation. During in vitro transformation of normal human fibroblast, upregulation of downregulates spindle checkpoint proteins as the mitotic checkpoint serine/threonine kinase budding uninhibited by benzimidazoles 1 (BUB1), the centromere protein F (CENPF) and the zw10 kinetochore protein (ZW10), compromising the chromosome alignment at the metaphase plate and leading to aneuploidy in daughter cells. Here we show that the heterogeneous nuclear ribonucleoprotein L (HNRNPL) binds to the polymorphic marker D2S1888 at the 3'UTR of gene, impairs the targeting, and restores BUB1 expression in chronic lymphocytic leukemia. This mechanism occurs at advanced passages of cell transformation and allows the expansion of more favorable clones. Our findings have revealed, at least in part, the molecular mechanisms behind the chromosomal stabilization of cell lines and the concept that, to survive, tumor cells cannot continuously change their genetic heritage but need to stabilize the most suitable karyotype.
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http://dx.doi.org/10.3390/cancers11040575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520824PMC
April 2019

Efficacy results of a phase 2 trial of first-line idelalisib plus ofatumumab in chronic lymphocytic leukemia.

Blood Adv 2019 04;3(7):1167-1174

Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.

PI3 kinase (PI3K) activity is critical for survival of neoplastic B cells in patients with chronic lymphocytic leukemia (CLL). Blockade of PI3K signaling with idelalisib is effective for the treatment of relapsed CLL in combination with the anti-CD20 antibody ofatumumab. In this single-arm, open-label, nonrandomized phase 2 study, we investigated the efficacy and safety of idelalisib with ofatumumab in 27 patients with treatment-naïve CLL in need of therapy. Patients were planned to receive idelalisib for 2 monthly cycles, then idelalisib and ofatumumab for 6 cycles, followed by idelalisib indefinitely. The study was closed early and all patients ceased therapy when an increased rate of death as a result of infection was observed on other first-line idelalisib trials. Median time on therapy was 8.1 months, and median duration of follow-up was 39.7 months. We previously reported high rates of hepatotoxicity in a smaller cohort of patients in this trial; toxicities necessitated therapy discontinuation in 15 patients after a median of 7.7 months. The most frequent grade ≥3 adverse events were transaminitis (52% of patients), neutropenia (33%), and colitis/diarrhea (15%). The best overall response rate (ORR) was 88.9%, including 1 complete response. Median progression-free survival (PFS) was 23 months (95% confidence interval [CI], 18-36 months); 11 patients have not yet required second-line therapy. Idelalisib and ofatumumab demonstrated an unacceptable safety profile in the first-line setting, which resulted in a short PFS despite a high ORR. Future development of PI3K inhibitors for use in treatment-naïve CLL will require novel approaches to mitigate toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02135133.
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http://dx.doi.org/10.1182/bloodadvances.2018030221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457234PMC
April 2019

Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia.

Blood 2019 06 28;133(25):2651-2663. Epub 2019 Mar 28.

Moores Cancer Center, University of California San Diego, La Jolla, CA.

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ test, < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1 Patients with GLI1 CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1 CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.
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http://dx.doi.org/10.1182/blood-2018-09-873695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587306PMC
June 2019

A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion.

Cancer Cell 2019 02 31;35(2):283-296.e5. Epub 2019 Jan 31.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA, USA. Electronic address:

SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor signaling, which we also identified in human CLL cases. Notably, human CLLs harboring SF3B1 mutations exhibit altered response to BTK inhibition. Our murine model of CLL thus provides insights into human CLL disease mechanisms and treatment.
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http://dx.doi.org/10.1016/j.ccell.2018.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372356PMC
February 2019

SET alpha and SET beta mRNA isoforms in chronic lymphocytic leukaemia.

Br J Haematol 2019 02 15;184(4):605-615. Epub 2018 Nov 15.

Duke University Medical Center, Durham, NC, USA.

Alteration in RNA splicing is implicated in carcinogenesis and progression. Mutations in spliceosome genes and alternative splicing of other genes have been noted in chronic lymphocytic leukaemia (CLL), a common B cell malignancy with heterogeneous outcomes. We previously demonstrated that differences in the amount of SET oncoprotein (a physiological inhibitor of the serine/threonine phosphatase, PP2A) is associated with clinical aggressiveness in patients with CLL. It is unknown if alternative splicing of gene transcripts regulating kinases and phosphatases affects disease pathobiology and CLL progression. We show here for the first time that mRNA levels of the alternatively spliced SET isoforms, SETA and SETB (SETα and SETβ), significantly correlate with disease severity (overall survival and time-to-first-treatment) in CLL patients. In addition, we demonstrate that relative increase of SETA to SETB mRNA can discriminate patients with a more aggressive disease course within the otherwise favourable CLL risk classifications of IGHV mutated and favourable hierarchical fluorescence in situ hybridisation groups. We validate our finding by showing comparable relationships of SET mRNA with disease outcomes using samples from an independent CLL cohort from a separate institution. These findings indicate that alternative splicing of SET, and potentially other signalling cascade molecules, influences CLL biology and patient outcomes.
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http://dx.doi.org/10.1111/bjh.15677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375670PMC
February 2019

Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies.

JCI Insight 2018 10 4;3(19). Epub 2018 Oct 4.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eμ-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.
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http://dx.doi.org/10.1172/jci.insight.121438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237462PMC
October 2018

and expression predicts Richter syndrome in chronic lymphocytic leukemia patients.

Blood 2018 11 21;132(20):2179-2182. Epub 2018 Sep 21.

Department of Cancer Biology and Medical Genetics and.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. It is characterized by the accumulation of CD19/CD5 lymphocytes and can have variable outcomes. Richter syndrome (RS) is a lethal complication in CLL patients that results in aggressive B-cell lymphomas, and there are no tests to predict its occurrence. Because alterations in microRNA expression can predict the development and progression of several cancers, we investigated whether dysregulation of specific microRNAs can predict RS in CLL patients. Thus, we compared microRNA expression levels in samples from 49 CLL patients who later developed RS with samples from 59 CLL patients who did not. We found that high expression of or low expression of can predict ∼50% of RS with a false positive rate of ∼9%. We found that CLL patients predicted to develop RS show either an increase of expression (∼20-fold) or a decrease of expression (∼21-fold) compared with CLL patients that are not predicted to develop RS. Thus, and can be valuable predictor markers of RS and have the potential to provide physicians with information that can indicate the best therapeutic strategy for CLL patients.
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http://dx.doi.org/10.1182/blood-2018-04-845115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238191PMC
November 2018

Cirmtuzumab inhibits ibrutinib-resistant, Wnt5a-induced Rac1 activation and proliferation in mantle cell lymphoma.

Oncotarget 2018 May 15;9(37):24731-24736. Epub 2018 May 15.

Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.

Cirmtuzumab may enhance the therapeutic activity of ibrutinib by inhibiting ROR1-dependent signaling pathway in patients with chronic lymphocytic leukemia (CLL). Mantle cell lymphoma (MCL) is B-cell malignancy that also expresses ROR1. In this study, we found that the plasma of patients with MCL had high levels of Wnt5a, a ROR1 ligand, that were comparable to those found in patients with CLL; in contrast Wnt5a was virtually undetectable in the plasma of age-matched healthy adults. We also found that Wnt5a induced Rac1 activation in the primary MCL cells. Cirmtuzumab, but not ibrutinib, could inhibit the capacity of Wnt5a to induce primary MCL cells to activate Rac1. Addition of exogenous Wnt5a significantly enhanced the numbers of MCL cell divisions and the proportion of dividing MCL cells entering S/G2 in MCL cells over time in the presence of CD154 and IL-4/10. Treatment of the MCL cells with cirmtuzumab, but not ibrutinib, blocked Wnt5a-enhanced proliferation of MCL cells. This study indicates that cirmtuzumab and ibrutinib may have complementary activity in the treatment of patients with MCL.
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http://dx.doi.org/10.18632/oncotarget.25340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973864PMC
May 2018

Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia.

Cell Stem Cell 2018 Jun;22(6):951-959.e3

Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; CIRM Alpha Stem Cell Clinic at University of California, San Diego, and Sanford Stem Cell Clinical Center, La Jolla, CA 92037-0695, USA; Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

Cirmtuzumab is a humanized monoclonal antibody (mAb) that targets ROR1, an oncoembryonic orphan receptor for Wnt5a found on cancer stem cells (CSCs). Aberrant expression of ROR1 is seen in many malignancies and has been linked to Rho-GTPase activation and cancer stem cell self-renewal. For patients with chronic lymphocytic leukemia (CLL), self-renewing, neoplastic B cells express ROR1 in 95% of cases. High-level leukemia cell expression of ROR1 is associated with an unfavorable prognosis. We conducted a phase 1 study involving 26 patients with progressive, relapsed, or refractory CLL. Patients received four biweekly infusions, with doses ranging from 0.015 to 20 mg/kg. Cirmtuzumab had a long plasma half-life and did not have dose-limiting toxicity. Inhibition of ROR1 signaling was observed, including decreased activation of RhoA and HS1. Transcriptome analyses showed that therapy inhibited CLL stemness gene expression signatures in vivo. Cirmtuzumab is safe and effective at inhibiting tumor cell ROR1 signaling in patients with CLL.
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http://dx.doi.org/10.1016/j.stem.2018.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001723PMC
June 2018

Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia.

Blood 2018 07 20;132(2):170-178. Epub 2018 Apr 20.

Moores Cancer Center and.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic protein expressed on chronic lymphocytic leukemia (CLL) that can serve as a receptor for Wnt5a, which can promote leukemia cell migration, proliferation, and survival. We found Wnt5a could induce ROR1 to complex with DOCK2 (dedicator of cytokinesis 2) and induce activation of Rac1/2; these effects could be blocked by cirmtuzumab, a humanized anti-ROR1 monoclonal antibody. We find that silencing DOCK2 specifically impaired the capacity of Wnt5a to induce activation of Rac1/2 or enhance CLL cell proliferation. We generated truncated forms of ROR1 and found the cytoplasmic proline-rich domain (PRD) of ROR1 was required for Wnt5a to induce ROR1 to complex with DOCK2 and activate Rac1/2 in the CLL cell-line MEC1. We introduced single amino acid substitutions of proline (P) to alanine (A) in the ROR1-PRD at potential binding sites for the Src-homology 3 domain of DOCK2. In contrast to wild-type ROR1, or other ROR1 P→A variants, ROR1 was unable to recruit DOCK2 in response to Wnt5a. Moreover, unlike MEC1 cells transfected with wild-type ROR1 or ROR1 with P→A substitutions at positions 784, 826, or 841, MEC1 cells transfected to express ROR1 did not have a growth advantage over MEC1 cells that do not express ROR1. This study reveals that the recruitment of DOCK2 may be critical for the capacity of Wnt5a to enhance CLL proliferation, which may contribute to the observed increased tendency for disease progression in patients who have CLL cells that express high levels of ROR1.
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http://dx.doi.org/10.1182/blood-2017-12-819383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043980PMC
July 2018

dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia.

Proc Natl Acad Sci U S A 2017 10 18;114(40):10731-10736. Epub 2017 Sep 18.

Department of Cancer Biology and Medical Genetics, The Ohio State University, Columbus, OH 43210;

Loss of is the most common genetic lesion in chronic lymphocytic leukemia (CLL), promoting overexpression of , which factors in leukemia pathogenesis. Indeed, an inhibitor of Bcl2, venetoclcax, is highly active in the treatment of patients with CLL. However, single-agent venetoclcax fails to eradicate minimal residual disease in most patients. Accordingly, we were interested in other genes that may be regulated by , which may target other drivers in CLL. We found that targets , which encodes an onco-embryonic surface protein expressed on the CLL cells of over 90% of patients, but not on virtually all normal postpartum tissues. CLL with high-level expression of ROR1 also have high-level expression of Bcl2, but low-to-negligible Moreover, CLL cases with high-level ROR1 have deletion(s) at the chromosomal location of the genes encoding (13q14) more frequently than cases with low-to-negligible ROR1, implying that deletion of may promote overexpression of , in addition to ROR1 is a receptor for Wnt5a, which can promote leukemia-cell proliferation and survival, and can be targeted by cirmtuzumab, a humanized anti-ROR1 mAb. We find that this mAb can enhance the in vitro cytotoxic activity of venetoclcax for CLL cells with high-level expression of ROR1, indicating that combining these agents, which target ROR1 and Bcl2, may have additive, if not synergistic, activity in patients with this disease.
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http://dx.doi.org/10.1073/pnas.1708264114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635897PMC
October 2017

Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia.

J Hematol Oncol 2017 05 19;10(1):112. Epub 2017 May 19.

Moores Cancer Center, University of California San Diego, 3855 Health Science Drive, La Jolla, CA, 92093-0820, USA.

Background: The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL.

Methods: Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model.

Results: PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine.

Conclusions: We show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients.
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http://dx.doi.org/10.1186/s13045-017-0435-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438492PMC
May 2017

The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia.

Oncotarget 2017 Apr;8(16):25942-25954

Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.

The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy (E2997). High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage.
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http://dx.doi.org/10.18632/oncotarget.15401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432228PMC
April 2017

Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia.

Cancer Cell 2016 Nov 3;30(5):750-763. Epub 2016 Nov 3.

Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways.
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http://dx.doi.org/10.1016/j.ccell.2016.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127278PMC
November 2016

High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia.

Blood 2016 12 4;128(25):2931-2940. Epub 2016 Nov 4.

Department of Medicine, Moores Cancer Center, University of California, San Diego, San Diego, CA.

ROR1 is an oncoembryonic orphan receptor found on chronic lymphocytic leukemia (CLL) B cells, but not on normal postpartum tissues. ROR1 is a receptor for Wnt5a that may complex with TCL1, a coactivator of AKT that is able to promote development of CLL. We found the CLL cells of a few patients expressed negligible ROR1 (ROR1), but expressed TCL1A at levels comparable to those of samples that expressed ROR1 (ROR1). Transcriptome analyses revealed that ROR1 cases generally could be distinguished from those that were ROR1 in unsupervised gene-expression clustering analysis. Gene-set enrichment analyses demonstrated that ROR1 CLL had lower expression and activation of AKT signaling pathways relative to ROR1 CLL, similar to what was noted for leukemia that respectively developed in TCL1 vs ROR1xTCL1 transgenic mice. In contrast to its effect on ROR1 CLL, Wnt5a did not enhance the proliferation, chemotaxis, or survival of ROR1 CLL. We examined the CLL cells from 1568 patients, which we randomly assigned to a training or validation set of 797 or 771 cases, respectively. Using recursive partitioning, we defined a threshold for ROR1 surface expression that could segregate samples of the training set into ROR1-Hi vs ROR1-Lo subgroups that differed significantly in their median treatment-free survival (TFS). Using this threshold, we found that ROR1-Hi cases had a significantly shorter median TFS and overall survival than ROR1-Lo cases in the validation set. These data demonstrate that expression of ROR1 may promote leukemia-cell activation and survival and enhance disease progression in patients with CLL.
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http://dx.doi.org/10.1182/blood-2016-04-712562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179332PMC
December 2016

Selectivity in Small Molecule Splicing Modulation.

ACS Chem Biol 2016 10 8;11(10):2716-2723. Epub 2016 Aug 8.

The Moores Cancer Center, University of California San Diego , La Jolla, California 92093, United States.

The dysregulation of RNA splicing is a molecular hallmark of disease, including different and often complex cancers. While gaining recognition as a target for therapeutic discovery, understanding the complex mechanisms guiding RNA splicing remains a challenge for chemical biology. The discovery of small molecule splicing modulators has recently enabled an evaluation of the mechanisms of aberrant splicing. We now report on three unique features within the selectivity of splicing modulators. First, we provide evidence that structural modifications within a splicing modulator can alter the splicing of introns in specific genes differently. These studies indicate that structure activity relationships not only have an effect on splicing activity but also include specificity for specific introns within different genes. Second, we find that these splicing modulators also target the mRNAs encoding components of the spliceosome itself. Remarkably, this effect includes the genes for the SF3B complex, a target of pladienolide B and related splicing modulators. Finally, we report on the first observation of a temporal phenomenon associated with small molecule splicing modulation. Combined, these three observations provide an important new perspective for the exploration of splicing modulation in terms of both future medicinal chemistry programs as well as understanding the key facets underlying its timing.
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http://dx.doi.org/10.1021/acschembio.6b00399DOI Listing
October 2016

Biomarkers in chronic lymphocytic leukemia: Clinical applications and prognostic markers.

Best Pract Res Clin Haematol 2016 03 10;29(1):79-89. Epub 2016 Aug 10.

Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA, USA.

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. The Rai and Binet staging systems are often used to predict survival. However, they do not take into account other biological characteristics of CLL cells that may influence the disease course and response to treatment. Prognostic factors such as chromosome abnormalities (trisomy 12, 11q deletions and 17p deletions), β2 microglobulin, thymidine kinase, CD38 and ZAP-70 expression, IGHV mutation status, and mutations in genes such as NOTCH1, MYD88, SF3B1, and ATM are also predictors of prognosis. These biological markers have enabled the development of multiparameter risk models to predict overall survival. In addition, these models are useful for treatment decisions, as they can identify patients that could be treated with clinical trials vs. standard of care therapies. This chapter will review the most important prognostic markers that have been described in CLL and their application in clinical practice.
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http://dx.doi.org/10.1016/j.beha.2016.08.005DOI Listing
March 2016

Dysregulation of a family of short noncoding RNAs, tsRNAs, in human cancer.

Proc Natl Acad Sci U S A 2016 May 11;113(18):5071-6. Epub 2016 Apr 11.

Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210; Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;

Chronic lymphocytic leukemia (CLL) is the most common human leukemia, and transgenic mouse studies indicate that activation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease. While studying the regulation of TCL1 expression, we identified the microRNA cluster miR-4521/3676 and discovered that these two microRNAs are associated with tRNA sequences and that this region can produce two small RNAs, members of a recently identified class of small noncoding RNAs, tRNA-derived small RNAs (tsRNAs). We further proved that miR-3676 and miR-4521 are tsRNAs using Northern blot analysis. We found that, like ts-3676, ts-4521 is down-regulated and mutated in CLL. Analysis of lung cancer samples revealed that both ts-3676 and ts-4521 are down-regulated and mutated in patient tumor samples. Because tsRNAs are similar in nature to piRNAs [P-element-induced wimpy testis (Piwi)-interacting small RNAs], we investigated whether ts-3676 and ts-4521 can interact with Piwi proteins and found these two tsRNAs in complexes containing Piwi-like protein 2 (PIWIL2). To determine whether other tsRNAs are involved in cancer, we generated a custom microarray chip containing 120 tsRNAs 16 bp or more in size. Microarray hybridization experiments revealed tsRNA signatures in CLL and lung cancer, indicating that, like microRNAs, tsRNAs may have an oncogenic and/or tumor-suppressor function in hematopoietic malignancies and solid tumors. Thus, our results show that tsRNAs are dysregulated in human cancer.
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http://dx.doi.org/10.1073/pnas.1604266113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983805PMC
May 2016
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