Publications by authors named "Michael Y Choi"

29 Publications

  • Page 1 of 1

Author Correction: Hepatic stellate cells secrete Ccl5 to induce hepatocyte steatosis.

Sci Rep 2020 Jun 19;10(1):10284. Epub 2020 Jun 19.

Department of Medicine, Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-67553-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303110PMC
June 2020

Targeted Therapy in Chronic Lymphocytic Leukemia.

Cancer J 2019 Nov/Dec;25(6):378-385

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

Despite a prevailing view that advances in cancer therapy will come through selective targeting of enzymes encoded by mutated oncogenes responsible for the neoplastic phenotype, recent advances in the treatment of patients with chronic lymphocytic leukemia (CLL) have instead exploited knowledge of its biology. Indeed, CLL cells depend on interactions with cells and soluble factors present in the tumor microenvironment for proliferation and survival. B-cell receptor signaling and chemokine-receptor signaling play prominent roles. Elucidation of these signaling pathways has defined physiologic targets for drugs, such as ibrutinib, which inhibit Bruton tyrosine kinase and are therapeutically effective. The characteristic high-level expression of BCL2 in CLL that can enhance leukemia-cell survival has now become an Achilles heel targeted by clinically effective drugs such as venetoclax. Here we discuss advances in such targeted therapy and highlight other disease attributes, such as the distinctive expression of ROR1, which may be targeted for clinical benefit, alone or in combination with other targeted therapies.
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http://dx.doi.org/10.1097/PPO.0000000000000416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039327PMC
August 2020

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

SOHO State of the Art Updates and Next Questions: The Conundrum in Assessing the Therapy Response of Patients With Chronic Lymphocytic Leukemia.

Clin Lymphoma Myeloma Leuk 2019 06 29;19(6):321-325. Epub 2019 May 29.

Division of Hematology/Oncology, UC San Diego Moores Cancer Center, La Jolla, CA. Electronic address:

In 2018, the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) updated the guidelines for diagnosis, indications for treatment, response assessment, and supportive management of patients with chronic lymphocytic leukemia. Included were definitions for response, which incorporated consideration of the significance of minimal residual disease. Here we discuss the clinical significance of complete response or partial response, as defined in the 2018 iwCLL guidelines, and the relative value of assessing for minimal residual disease.
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http://dx.doi.org/10.1016/j.clml.2019.05.013DOI Listing
June 2019

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

Hepatic stellate cells secrete Ccl5 to induce hepatocyte steatosis.

Sci Rep 2018 05 14;8(1):7499. Epub 2018 May 14.

Department of Medicine, Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of disease severity, starting from pure steatosis, leading to fatty inflammation labeled as non-alcoholic steatohepatitis (NASH), and finally fibrosis leading to cirrhosis. Activated hepatic stellate cells (HSCs) are known to contribute to fibrosis, but less is known about their function during NAFLD's early stages prior to fibrosis. We developed an ex vivo assay that cocultures primary HSCs from mouse models of liver disease with healthy hepatocytes to study their interaction. Our data indicate that chemokine Ccl5 is one of the HSC-secreted mediators in early NASH in humans and in mice fed with choline-deficient, L-amino acid defined, high fat diet. Furthermore, Ccl5 directly induces steatosis and pro-inflammatory factors in healthy hepatocytes through the receptor Ccr5. Although Ccl5 is already known to be secreted by many liver cell types including HSCs and its pro-fibrotic role well characterized, its pro-steatotic action has not been recognized until now. Similarly, the function of HSCs in fibrogenesis is widely accepted, but their pro-steatotic role has been unclear. Our result suggests that in early NASH, HSCs secrete Ccl5 which contributes to a broad array of mechanisms by which hepatic steatosis and inflammation are achieved.
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http://dx.doi.org/10.1038/s41598-018-25699-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951796PMC
May 2018

JAK2 V617F mutation in plasma cell-free DNA preceding clinically overt myelofibrosis: Implications for early diagnosis.

Cancer Biol Ther 2018 08;19(8):664-668

a Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine , University of California San Diego Moores Cancer Center , La Jolla , CA , USA.

A 52 year-old man with Erdheim-Chester Disease (ECD) (a non-Langerhans polyostotic sclerosing histiocytosis) had next-generation sequencing (NGS) performed as part of his diagnostic workup. In addition to the tissue BRAF V600E mutation that is found in over 50% of ECD cases, he was also found to have a JAK2 V617F alteration in cell-free circulating tumor DNA (ctDNA) (liquid biopsy). The latter was thought to be an "incidental" finding, perhaps due to clonal hematopoiesis (though this usually occurs in older individuals), as his blood counts were normal and he had no splenomegaly. Approximately 13 months after the ctDNA test showing JAK2 V617F, he developed anemia, thrombocytopenia, and splenomegaly. Marrow biopsy then showed megakaryocytic atypia and markedly increased marrow fibrosis, consistent with WHO grade 2 of 3 myelofibrosis. Therefore, the patient was determined to have ECD with a typical BRAF V600E mutation, as well as primary myelofibrosis, with the latter diagnosis manifesting clinically over one year after the JAK2 V617F was first detected in ctDNA. He recently was started on the JAK2 inhibitor ruxolitinib. This case demonstrates that genomic alterations detected by liquid biopsy for evaluation of specific malignancies already present may serve as an early harbinger of hematological disease.
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http://dx.doi.org/10.1080/15384047.2018.1450120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067874PMC
August 2018

BRAF mutation as a novel driver of eosinophilic cystitis.

Cancer Biol Ther 2017 Sep 22;18(9):655-659. Epub 2017 Aug 22.

a Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center , University of California, San Diego , 3855 Health Sciences Drive #0820, La Jolla , CA.

Eosinophilic cystitis is a rare manifestation of hypereosinophilia and a cause of morbidity, including dysuria and hematuria. Although some cases can be attributed to infection or allergy, most cases are assessed to be idiopathic and treated with corticosteroids. However, hypereosinophilia can also be due to actionable clonal molecular alterations in the haematopoietic cells, similar to other myeloproliferative neoplasms. Common mutations associated with eosonophilic syndromes are of platelet-derived growth factor receptor α or β or c-kit, though other pathogenic mutations have been found by next generation sequencing. Determination of a specific mutation may therefore identify clonality and refine treatment of some cases. Here we review the molecular features of eosinophilic disorders. We also describe the use of a liquid biopsy of circulating cell-free DNA in the workup of a case of eosinophilic cystitis in which next generation sequencing of cell-free DNA showed a BRAF I463T mutation. In silico modeling supports the functional impact and potential clinical relevance of BRAF I463T.
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http://dx.doi.org/10.1080/15384047.2017.1360449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663411PMC
September 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

Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice.

Dig Dis Sci 2017 08 19;62(8):2021-2034. Epub 2017 Apr 19.

Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA.

Background And Aims: Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease.

Methods: Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease.

Results: Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes.

Conclusions: IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.
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http://dx.doi.org/10.1007/s10620-017-4576-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684583PMC
August 2017

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.

Lancet Oncol 2017 Feb 13;18(2):230-240. Epub 2017 Jan 13.

Victorian Comprehensive Cancer Centre, Parkville, Melbourne, VIC, Australia; Faculty of Medicine, University of Melbourne, Parkville, Melbourne, VIC, Australia; Department of Clinical Haematology and BMT, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia; Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, VIC, Australia.

Background: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab.

Methods: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m in month 1 and 500 mg/m in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616.

Findings: Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax.

Interpretation: A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies.

Funding: AbbVie Inc and Genentech Inc.
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http://dx.doi.org/10.1016/S1470-2045(17)30012-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316338PMC
February 2017

The chronic lymphocytic leukemia microenvironment: Beyond the B-cell receptor.

Best Pract Res Clin Haematol 2016 03 11;29(1):40-53. Epub 2016 Aug 11.

Moores Cancer Center, UCSD-Moores Cancer Center, La Jolla, 92093-0820, CA, USA. Electronic address:

Malignant B cells accumulate in the peripheral blood, bone marrow, and lymphoid organs of patients with chronic lymphocytic leukemia (CLL). In the tissue compartments, CLL shape a protective microenvironment by coopting normal elements. The efficacy of drugs that target these interactions further underscores their importance in the pathogenesis of CLL. While the B cell receptor (BCR) pathway clearly plays a central role in the CLL microenvironment, there is also rationale to evaluate agents that inhibit other aspects or modulate the immune cells in the microenvironment. Here we review the main cellular components, soluble factors, and signaling pathways of the CLL microenvironment, and highlight recent clinical advances. As the BCR pathway is reviewed elsewhere, we focus on other aspects of the microenvironment.
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http://dx.doi.org/10.1016/j.beha.2016.08.007DOI Listing
March 2016

DIGIT Is a Conserved Long Noncoding RNA that Regulates GSC Expression to Control Definitive Endoderm Differentiation of Embryonic Stem Cells.

Cell Rep 2016 10;17(2):353-365

Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address:

Long noncoding RNAs (lncRNAs) exhibit diverse functions, including regulation of development. Here, we combine genome-wide mapping of SMAD3 occupancy with expression analysis to identify lncRNAs induced by activin signaling during endoderm differentiation of human embryonic stem cells (hESCs). We find that DIGIT is divergent to Goosecoid (GSC) and expressed during endoderm differentiation. Deletion of the SMAD3-occupied enhancer proximal to DIGIT inhibits DIGIT and GSC expression and definitive endoderm differentiation. Disruption of the gene encoding DIGIT and depletion of the DIGIT transcript reveal that DIGIT is required for definitive endoderm differentiation. In addition, we identify the mouse ortholog of DIGIT and show that it is expressed during development and promotes definitive endoderm differentiation of mouse ESCs. DIGIT regulates GSC in trans, and activation of endogenous GSC expression is sufficient to rescue definitive endoderm differentiation in DIGIT-deficient hESCs. Our study defines DIGIT as a conserved noncoding developmental regulator of definitive endoderm.
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http://dx.doi.org/10.1016/j.celrep.2016.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120872PMC
October 2016

How Do Targeted Therapies Change the Management of Indolent Lymphomas?

Oncology (Williston Park) 2016 09;30(9):859-60

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September 2016

Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway.

Oncotarget 2016 Jan;7(3):2809-22

UCSD-Moores Cancer Center, La Jolla, CA, USA.

The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma--CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor--Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high-risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies.
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http://dx.doi.org/10.18632/oncotarget.6465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823073PMC
January 2016

Pre-clinical Specificity and Safety of UC-961, a First-In-Class Monoclonal Antibody Targeting ROR1.

Clin Lymphoma Myeloma Leuk 2015 Jun;15 Suppl:S167-9

Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA. Electronic address:

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen. Because of its expression on the cell surface of leukemia cells from patients with chronic lymphocytic leukemia (CLL), but not on normal B-cells or other postpartum tissues, ROR1 is an attractive candidate for targeted therapies. UC-961 is a first-in-class humanized monoclonal antibody that binds the extracellular domain of ROR1. In this article we outline some of the preclinical studies leading to an investigational new drug designation, enabling clinical studies in patients with CLL.
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http://dx.doi.org/10.1016/j.clml.2015.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548279PMC
June 2015

AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody-Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML.

Mol Cancer Ther 2015 Jul 1;14(7):1650-60. Epub 2015 May 1.

Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, California.

CD37 is a tetraspanin expressed on malignant B cells. Recently, CD37 has gained interest as a therapeutic target. We developed AGS67E, an antibody-drug conjugate that targets CD37 for the potential treatment of B/T-cell malignancies. It is a fully human monoclonal IgG2 antibody (AGS67C) conjugated, via a protease-cleavable linker, to the microtubule-disrupting agent monomethyl auristatin E (MMAE). AGS67E induces potent cytotoxicity, apoptosis, and cell-cycle alterations in many non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) cell lines and patient-derived samples in vitro. It also shows potent antitumor activity in NHL and CLL xenografts, including Rituxan-refractory models. During profiling studies to confirm the reported expression of CD37 in normal tissues and B-cell malignancies, we made the novel discovery that the CD37 protein was expressed in T-cell lymphomas and in AML. AGS67E bound to >80% of NHL and T-cell lymphomas, 100% of CLL and 100% of AML patient-derived samples, including CD34(+)CD38(-) leukemic stem cells. It also induced cytotoxicity, apoptosis, and cell-cycle alterations in AML cell lines and antitumor efficacy in orthotopic AML xenografts. Taken together, this study shows not only that AGS67E may serve as a potential therapeutic for B/T-cell malignancies, but it also demonstrates, for the first time, that CD37 is well expressed and a potential drug target in AML.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557793PMC
July 2015

Update on non-canonical microRNAs.

Biomol Concepts 2014 Aug;5(4):275-87

Non-canonical microRNAs are a recently-discovered subset of microRNAs. They structurally and functionally resemble canonical miRNAs, but were found to follow distinct maturation pathways, typically bypassing one or more steps of the classic canonical biogenesis pathway. Non-canonical miRNAs were found to have diverse origins, including introns, snoRNAs, endogenous shRNAs and tRNAs. Our knowledge about their functions remains relatively primitive; however, many interesting discoveries have taken place in the past few years. They have been found to take part in several cellular processes, such as immune response and stem cell proliferation. Adversely, their deregulation has pathologic effects on several different tissues, which strongly suggests an integral role for non-canonical miRNAs in disease pathogenesis. In this review, we discuss the recently-discovered functional characteristics of non-canonical miRNAs and illustrate their principal maturation pathways as well as debating their potential role in multiple cellular processes.
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http://dx.doi.org/10.1515/bmc-2014-0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343302PMC
August 2014

Potent fluorinated agelastatin analogues for chronic lymphocytic leukemia: design, synthesis, and pharmacokinetic studies.

J Med Chem 2014 Jun 10;57(12):5085-93. Epub 2014 Jun 10.

Department of Chemistry and Biochemistry, ‡Skaggs School of Pharmacy and Pharmaceutical Sciences, §Moores Cancer Center, and ⊥School of Medicine, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093-0358, United States.

Chronic lymphocytic leukemia (CLL) is the most common lymphoid neoplasia in Western societies and is currently incurable. Multiple treatment options are practiced, but the available small molecule drugs suffer from dose-limiting toxicity and undesirable side effects. The need for new, less toxic treatments is a pressing concern. Here, we demonstrate that (-)-agelastatin A (1a), a pyrrole-imidazole alkaloid obtained from a marine sponge, exhibits potent in vitro activity against primary cell lines of CLL and disclose the synthesis of several analogues that are equipotent or exceed the potency of the natural product. The novel synthetic analogue, 13-debromo-13-trifluoromethyl agelastatin A (1j), showed higher activity than the natural product when tested against the same cell lines and is the most potent agelastatin derivative reported to date. A detailed in vitro structure-activity relationship of 1a in CLL compared to that of 22 synthetic analogues is described along with preliminary in vivo pharmacokinetic and metabolism studies on the most potent compounds.
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http://dx.doi.org/10.1021/jm4016922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079331PMC
June 2014

Inhibitors of B-cell receptor signaling for patients with B-cell malignancies.

Cancer J 2012 Sep-Oct;18(5):404-10

UC San Diego Moores Cancer Center, La Jolla, CA 92093, USA.

The B-cell receptor (BCR) complex and its associated protein tyrosine kinases play a critical role in the development, proliferation, and survival of normal or malignant B cells. Regulated activity of the BCR complex promotes the expansion of selected B cells and the deletion of unwanted or self-reactive ones. Compounds that inhibit various components of this pathway, including spleen tyrosine kinase, Bruton's tyrosine kinase, and phosphoinositol-3 kinase, have been developed. We summarize the rationale for use of agents that can inhibit BCR signaling to treat patients with either indolent or aggressive B-cell lymphomas, highlight early clinical results, and speculate on the future application of such agents in the treatment of patients with various B-cell lymphomas.
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http://dx.doi.org/10.1097/PPO.0b013e31826c5810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461329PMC
April 2013

Non-canonical microRNAs miR-320 and miR-702 promote proliferation in Dgcr8-deficient embryonic stem cells.

Biochem Biophys Res Commun 2012 Sep 19;426(2):183-9. Epub 2012 Aug 19.

Department of Medicine/GI Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

MicroRNAs are known to contribute significantly to stem cell phenotype by post-transcriptionally regulating gene expression. Most of our knowledge of microRNAs comes from the study of canonical microRNAs that require two sequential cleavages by the Drosha/Dgcr8 heterodimer and Dicer to generate mature products. In contrast, non-canonical microRNAs bypass the cleavage by the Drosha/Dgcr8 heterodimer within the nucleus but still require cytoplasmic cleavage by Dicer. The function of non-canonical microRNAs in embryonic stem cells (ESCs) remains obscure. It has been hypothesized that non-canonical microRNAs have important roles in ESCs based upon the phenotypes of ESC lines that lack these specific classes of microRNAs; Dicer-deficient ESCs lacking both canonical and non-canonical microRNAs have much more severe proliferation defect than Dgcr8-deficient ESCs lacking only canonical microRNAs. Using these cell lines, we identified two non-canonical microRNAs, miR-320 and miR-702, that promote proliferation of Dgcr8-deficient ESCs by releasing them from G1 arrest. This is accomplished by targeting the 3'-untranslated regions of the cell cycle inhibitors p57 and p21 and thereby inhibiting their expression. This is the first report of the crucial role of non-canonical microRNAs in ESCs.
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http://dx.doi.org/10.1016/j.bbrc.2012.08.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478954PMC
September 2012

MicroRNAs are indispensable for reprogramming mouse embryonic fibroblasts into induced stem cell-like cells.

PLoS One 2012 21;7(6):e39239. Epub 2012 Jun 21.

Department of Medicine/GI Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

MicroRNAs play a pivotal role in cellular maintenance, proliferation, and differentiation. They have also been implicated to play a key role in disease pathogenesis, and more recently, cellular reprogramming. Certain microRNA clusters can enhance or even directly induce reprogramming, while repressing key proteins involved in microRNA processing decreases reprogramming efficiency. Although microRNAs clearly play important roles in cellular reprogramming, it remains unknown whether microRNAs are absolutely necessary. We endeavored to answer this fundamental question by attempting to reprogram Dicer-null mouse embryonic fibroblasts (MEFs) that lack almost all functional microRNAs using a defined set of transcription factors. Transduction of reprogramming factors using either lentiviral or piggyBac transposon vector into two, independently derived lines of Dicer-null MEFs failed to produce cells resembling embryonic stem cells (ESCs). However, expression of human Dicer in the Dicer-null MEFs restored their reprogramming potential. Our study demonstrates for the first time that microRNAs are indispensable for dedifferentiation reprogramming.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039239PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380844PMC
December 2012

Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells.

Proc Natl Acad Sci U S A 2011 Aug 25;108(32):13253-7. Epub 2011 Jul 25.

University of California at San Diego Moores Cancer Center, La Jolla, CA 92093-0820, USA.

Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/β-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.
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http://dx.doi.org/10.1073/pnas.1110431108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156152PMC
August 2011

New insights into the role of Hedgehog signaling in gastrointestinal development and cancer.

Gastroenterology 2009 Aug 27;137(2):422-4. Epub 2009 Jun 27.

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http://dx.doi.org/10.1053/j.gastro.2009.06.021DOI Listing
August 2009

Expression and function of Nkx6.3 in vertebrate hindbrain.

Brain Res 2008 Jul 6;1222:42-50. Epub 2008 May 6.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, USA.

Homeodomain transcription factors serve important functions in organogenesis and tissue differentiation, particularly with respect to the positional identity of individual cells. The Nkx6 subfamily controls tissue differentiation in the developing central nervous system where they function as transcriptional repressor proteins. Recent work indicates that Nkx6.3 is expressed in hindbrain V2 interneurons that co-express Nkx6.1, suggesting the possibility of functional redundancy. Here, we report that Nkx6.3 expression is specific to Chx10+ V2a interneurons but not to Gata3+ V2b interneurons of the hindbrain, and that Nkx6.3 expression appears to mark cells of the prospective medullary reticular formation. Molecular analysis of Nkx6.3 null embryonic mouse hindbrain did not reveal detectable defects in progenitor markers, motor neuron or V2 interneuron sub-types. Forced expression of Nkx6.3 and Nkx6.1 promote V2 interneuron differentiation in the developing chick hindbrain. These findings indicate Nkx6.3 function is dispensable for CNS development and lead to the proposal that absence of overt defects is due to functional compensation from a related homeodomain transcription factor.
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http://dx.doi.org/10.1016/j.brainres.2008.04.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2555971PMC
July 2008

Requirement of the tissue-restricted homeodomain transcription factor Nkx6.3 in differentiation of gastrin-producing G cells in the stomach antrum.

Mol Cell Biol 2008 May 17;28(10):3208-18. Epub 2008 Mar 17.

Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.

Many homeodomain transcription factors function in organogenesis and cell differentiation. The Nkx family illustrates these functions especially well, and the Nkx6 subfamily controls differentiation in the central nervous system and pancreas. Nkx6.3, a recent addition to this subfamily, overlaps Nkx6.1 and Nkx6.2 in expression in the hindbrain and stomach. Nkx6.3 transcripts localize in the epithelium of the most distal stomach region, the antrum and pylorus; expression in the adult intestine is lower and confined to the proximal duodenum. Nkx6.3(-)(/)(-) mice develop and grow normally, with a grossly intact stomach and duodenum. These mice show markedly reduced gastrin mRNA, many fewer gastrin-producing (G) cells in the stomach antrum, hypogastrinemia, and increased stomach luminal pH, with a corresponding increase in somatostatin mRNA levels and antral somatostatin-producing (D) cells. They express normal levels of other transcription factors required for gastric endocrine cell differentiation, Pdx1, Pax6, and Ngn3; conversely, Ngn3(-)(/)(-) mice, which also show reduced gastrin levels, express Nkx6.3 normally. These studies implicate Nkx6.3 as a selective regulator of G- and D-cell lineages, which are believed to derive from a common progenitor, and suggest that it operates in parallel with Ngn3.
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http://dx.doi.org/10.1128/MCB.01737-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423174PMC
May 2008

A dynamic expression survey identifies transcription factors relevant in mouse digestive tract development.

Development 2006 Oct 13;133(20):4119-29. Epub 2006 Sep 13.

Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.

Tissue-restricted transcription factors (TFs), which confer specialized cellular properties, are usually identified through sequence homology or cis-element analysis of lineage-specific genes; conventional modes of mRNA profiling often fail to report non-abundant TF transcripts. We evaluated the dynamic expression during mouse gut organogenesis of 1381 transcripts, covering nearly every known and predicted TF, and documented the expression of approximately 1000 TF genes in gastrointestinal development. Despite distinctive structures and functions, the stomach and intestine exhibit limited differences in TF genes. Among differentially expressed transcripts, a few are virtually restricted to the digestive tract, including Nr2e3, previously regarded as a photoreceptor-specific product. TFs that are enriched in digestive organs commonly serve essential tissue-specific functions, hence justifying a search for other tissue-restricted TFs. Computational data mining and experimental investigation focused interest on a novel homeobox TF, Isx, which appears selectively in gut epithelium and mirrors expression of the intestinal TF Cdx2. Isx-deficient mice carry a specific defect in intestinal gene expression: dysregulation of the high density lipoprotein (HDL) receptor and cholesterol transporter scavenger receptor class B, type I (Scarb1). Thus, integration of developmental gene expression with biological assessment, as described here for TFs, represents a powerful tool to investigate control of tissue differentiation.
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http://dx.doi.org/10.1242/dev.02537DOI Listing
October 2006