Acute Myeloid Leukemia
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The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells
Published OnlineFirst May 2, 2019; DOI: 10.1158/2159-8290.CD-19-0125 RESEARCH ARTICLE The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells Tamilla Nechiporuk1,2, Stephen E. Kurtz1,2, Olga Nikolova2,3, Tingting Liu1,2, Courtney L. Jones4, Angelo D’Alessandro5, Rachel Culp-Hill5, Amanda d’Almeida1,2, Sunil K. Joshi1,2, Mara Rosenberg1,2, Cristina E. Tognon1,2,6, Alexey V. Danilov1,2, Brian J. Druker1,2,6, Bill H. Chang2,7, Shannon K. McWeeney2,8, and Jeffrey W. Tyner1,2,9 ABSTRACT To study mechanisms underlying resistance to the BCL2 inhibitor venetoclax in acute myeloid leukemia (AML), we used a genome-wide CRISPR/Cas9 screen to identify gene knockouts resulting in drug resistance. We validated TP53, BAX, and PMAIP1 as genes whose inactivation results in venetoclax resistance in AML cell lines. Resistance to venetoclax resulted from an inability to execute apoptosis driven by BAX loss, decreased expression of BCL2, and/or reliance on alternative BCL2 family members such as BCL2L1. The resistance was accompanied by changes in mitochondrial homeostasis and cellular metabolism. Evaluation of TP53 knockout cells for sensitivities to a panel of small-molecule inhibitors revealed a gain of sensitivity to TRK inhibitors. We relate these observations to patient drug responses and gene expression in the Beat AML dataset. Our results implicate TP53, the apoptotic network, and mitochondrial functionality as drivers of venetoclax response in AML and suggest strategies to overcome resistance. SIGNIFICANCE: AML is challenging to treat due to its heterogeneity, and single-agent therapies have universally failed, prompting a need for innovative drug combinations. -
Gy Total Body Irradiation Followed by Allogeneic Hematopoietic St
Bone Marrow Transplantation (2009) 44, 785–792 & 2009 Macmillan Publishers Limited All rights reserved 0268-3369/09 $32.00 www.nature.com/bmt ORIGINAL ARTICLE Fludarabine, amsacrine, high-dose cytarabine and 12 Gy total body irradiation followed by allogeneic hematopoietic stem cell transplantation is effective in patients with relapsed or high-risk acute lymphoblastic leukemia F Zohren, A Czibere, I Bruns, R Fenk, T Schroeder, T Gra¨f, R Haas and G Kobbe Department of Haematology, Oncology and Clinical Immunology, Heinrich Heine-University, Du¨sseldorf, Germany In this prospective study, we examined the toxicity and Introduction efficacy of an intensified conditioning regimen for treatment of patients with relapsed or high-risk acute The use of intensified conventional induction chemothera- lymphoblastic leukemia who undergo allogeneic hemato- pies in the treatment of newly diagnosed ALL in adult poietic stem cell transplantation. Fifteen patients received patients has led to initial CR rates of up to 90%. But, as fludarabine 30 mg/m2, cytarabine 2000 mg/m2, amsacrine some patients are even refractory to first-line therapy, the 100 mg/m2 on days -10, -9, -8 and -7, anti-thymocyte majority of the responding patients unfortunately suffer globulin (ATG-Fresenius) 20 mg/kg body weight on days from relapse. Therefore, the probability of long-term -6, -5 and -4 and fractionated total body irradiation disease-free survival is o30%.1–5 Risk stratification based 2 Â 2 Gy on days -3, -2 and -1 (FLAMSA-ATG-TBI) on prognostic factors allows identification of high-risk before allogeneic hematopoietic stem cell transplantation. ALL patients with poor prognosis.6–12 Myeloablative At the time of hematopoietic stem cell transplantation, 10 conditioning therapy followed by allogeneic hematopoietic patients were in complete remission (8 CR1; 2 CR2), 3 stem cell transplantation (HSCT) is currently the treatment with primary refractory and 2 suffered from refractory of choice for these high-risk patients.13–15 A combination of relapse. -
Clinical Outcome of FLAG-IDA Chemotherapy Sequential
Bone Marrow Transplantation (2019) 54:458–464 https://doi.org/10.1038/s41409-018-0283-5 ARTICLE Clinical outcome of FLAG-IDA chemotherapy sequential with Flu–Bu3 conditioning regimen in patients with refractory AML: a parallel study from Shanghai Institute of Hematology and Institut Paoli-Calmettes 1 2 3 2 3 2 1 Ling Wang ● Raynier Devillier ● Ming Wan ● Justine Decroocq ● Liang Tian ● Sabine Fürst ● Li-Ning Wang ● 2 1 2 1 Norbert Vey ● Xing Fan ● Didier Blaise ● Jiong Hu Received: 23 January 2018 / Revised: 28 June 2018 / Accepted: 30 June 2018 / Published online: 6 August 2018 © The Author(s) 2018. This article is published with open access Abstract The purpose of the study was to evaluate the feasibility of conditioning regimen with sequential chemotherapy (FLAG-IDA), followed by Fludarabine (5 days) + Busulfan (3 days) by parallel analysis of patients with refractory acute myeloid leukemia (AML) from two transplantation centers in China and France. A total of 47 refractory AML with median bone marrow blast of 35% (1–90%) and median age at 42 years (16–62) were enrolled. Thirteen patients received peripheral stem cell 1234567890();,: 1234567890();,: transplantation (HSCT) from HLA-matched sibling donor, while 18 and 16 from unrelated or haplo-identical donors, respectively. With a median follow-up of 24.3 months (1–70), 13 patients relapsed at a median time of 5.1 months (2.2–18.0) and 24 patients died due to relapse (n = 12) or non-relapsed mortality (NRM, n = 12). The estimated 3-year RR and NRM were 33.5 ± 5.7% and 25.7 ± 4.2%, respectively. -
Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug
cancers Article Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug Response Genes in Pediatric Acute Myeloid Leukemia David G.J. Cucchi 1 , Costa Bachas 1 , Marry M. van den Heuvel-Eibrink 2,3, Susan T.C.J.M. Arentsen-Peters 3, Zinia J. Kwidama 1, Gerrit J. Schuurhuis 1, Yehuda G. Assaraf 4, Valérie de Haas 3 , Gertjan J.L. Kaspers 3,5 and Jacqueline Cloos 1,* 1 Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; [email protected] (D.G.J.C.); [email protected] (C.B.); [email protected] (Z.J.K.); [email protected] (G.J.S.) 2 Department of Pediatric Oncology/Hematology, Erasmus MC–Sophia Children’s Hospital, 3015 CN Rotterdam, The Netherlands; [email protected] 3 Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; [email protected] (S.T.C.J.M.A.-P.); [email protected] (V.d.H.); [email protected] (G.J.L.K.) 4 The Fred Wyszkowski Cancer Research, Laboratory, Department of Biology, Technion-Israel Institute of Technology, 3200003 Haifa, Israel; [email protected] 5 Emma’s Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands * Correspondence: [email protected] Received: 21 April 2020; Accepted: 12 May 2020; Published: 15 May 2020 Abstract: Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
FLT3 Inhibitors in Acute Myeloid Leukemia Mei Wu1, Chuntuan Li2 and Xiongpeng Zhu2*
Wu et al. Journal of Hematology & Oncology (2018) 11:133 https://doi.org/10.1186/s13045-018-0675-4 REVIEW Open Access FLT3 inhibitors in acute myeloid leukemia Mei Wu1, Chuntuan Li2 and Xiongpeng Zhu2* Abstract FLT3 mutations are one of the most common findings in acute myeloid leukemia (AML). FLT3 inhibitors have been in active clinical development. Midostaurin as the first-in-class FLT3 inhibitor has been approved for treatment of patients with FLT3-mutated AML. In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents. Keywords: FMS-like tyrosine kinase 3 inhibitors, Acute myeloid leukemia, Midostaurin, FLT3 Introduction RAS, MEK, and PI3K/AKT pathways [10], and ultim- Acute myeloid leukemia (AML) remains a highly resist- ately causes suppression of apoptosis and differentiation ant disease to conventional chemotherapy, with a me- of leukemic cells, including dysregulation of leukemic dian survival of only 4 months for relapsed and/or cell proliferation [11]. refractory disease [1]. Molecular profiling by PCR and Multiple FLT3 inhibitors are in clinical trials for treat- next-generation sequencing has revealed a variety of re- ing patients with FLT3/ITD-mutated AML. In this re- current gene mutations [2–4]. New agents are rapidly view, we summarized the preclinical and clinical studies emerging as targeted therapy for high-risk AML [5, 6]. on new FLT3 inhibitors, including sorafenib, lestaurtinib, In 1996, FMS-like tyrosine kinase 3/internal tandem du- sunitinib, tandutinib, quizartinib, midostaurin, gilteriti- plication (FLT3/ITD) was first recognized as a frequently nib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG mutated gene in AML [7]. -
Transient Exposure to Quizartinib Mediates Sustained Inhibition of FLT3 Signaling While Specifically Inducing Apoptosis in FLT3-Activated Leukemia Cells
Published OnlineFirst February 14, 2013; DOI: 10.1158/1535-7163.MCT-12-0305 Molecular Cancer Cancer Therapeutics Insights Therapeutics Transient Exposure to Quizartinib Mediates Sustained Inhibition of FLT3 Signaling while Specifically Inducing Apoptosis in FLT3-Activated Leukemia Cells Ruwanthi N. Gunawardane, Ronald R. Nepomuceno, Allison M. Rooks, Jeremy P. Hunt, Jill M. Ricono, Barbara Belli, and Robert C. Armstrong Abstract Fms-like tyrosine kinase 3 (FLT3) is implicated in the pathogenesis of acute myeloid leukemia (AML). FLT3-activating internal tandem duplication (ITD) mutations are found in approximately 30% of patients with AML and are associated with poor outcome in this patient population. Quizartinib (AC220) has previously been shown to be a potent and selective FLT3 inhibitor. In the current study, we expand on previous observations by showing that quizartinib potently inhibits the phosphorylation of FLT3 and downstream signaling molecules independent of FLT3 genotype, yet induces loss of viability only in cells expressing constitutively activated FLT3. We further show that transient exposure to quizartinib, whether in vitro or in vivo, leads to prolonged inhibition of FLT3 signaling, induction of apoptosis, and drastic reductions in tumor volume and pharmacodynamic endpoints. In vitro experiments suggest that these prolonged effects are mediated by slow binding kinetics that provide for durable inhibition of the kinase following drug removal/clearance. Together these data suggest quizartinib, with its unique combination of selectivity and potent/sustained inhibition of FLT3, may provide a safe and effective treatment against FLT3-driven leukemia. Mol Cancer Ther; 12(4); 1–10. Ó2013 AACR. Introduction downstream signaling cascades including the Ras/ Fms-like tyrosine kinase 3 (FLT3) is a member of the MAPK, PI3K/Akt, and STAT5 pathways (1, 9–13). -
Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity
Published OnlineFirst July 18, 2019; DOI: 10.1158/1078-0432.CCR-19-0832 Translational Cancer Mechanisms and Therapy Clinical Cancer Research Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia Jun Ma1, Shoujing Zhao1, Xinan Qiao1, Tristan Knight2,3, Holly Edwards4,5, Lisa Polin4,5, Juiwanna Kushner4,5, Sijana H. Dzinic4,5, Kathryn White4,5, Guan Wang1, Lijing Zhao6, Hai Lin7, Yue Wang8, Jeffrey W. Taub2,3, and Yubin Ge3,4,5 Abstract Purpose: To investigate the efficacy of the combination of with venetoclax. Changes of Mcl-1 transcript levels were the FLT3 inhibitors midostaurin or gilteritinib with the Bcl-2 assessed by RT-PCR. inhibitor venetoclax in FLT3-internal tandem duplication Results: The combination of midostaurin or gilteritinib (ITD) acute myeloid leukemia (AML) and the underlying with venetoclax potently and synergistically induces apo- molecular mechanism. ptosis in FLT3-ITD AML cell lines and primary patient Experimental Design: Using both FLT3-ITD cell lines and samples. The FLT3 inhibitors induced downregulation of primary patient samples, Annexin V-FITC/propidium iodide Mcl-1, enhancing venetoclax activity. Phosphorylated-ERK staining and flow cytometry analysis were used to quantify cell expression is induced by venetoclax but abolished by the death induced by midostaurin or gilteritinib, alone or in combination of venetoclax with midostaurin or gilteritinib. combination with venetoclax. Western blot analysis was per- Simultaneous downregulation of Mcl-1 by midostaurin or formed to assess changes in protein expression levels of gilteritinib and inhibition of Bcl-2 by venetoclax results in members of the JAK/STAT, MAPK/ERK, and PI3K/AKT path- "free" Bim, leading to synergistic induction of apoptosis. -
Letters to the Editor
LETTERS TO THE EDITOR FLT3 inhibitor, sorafenib, induced no myelosuppression.5,6 Inhibition of c-Kit by tyrosine kinase inhibitors To better understand the relationship between inhibition of c-Kit, FLT3, and marrow suppression, we studied a series of different TKIs using bone marrow progenitor cell assays Several small molecule tyrosine kinase inhibitors (TKIs) and immunoblots. inhibit c-Kit, an effect associated with myelosuppression Cell lines were cultured as previously described.2 TF-1 and hair depigmentation. We studied a panel of approved cells were obtained from the American Type Culture and investigational TKIs for inhibitory activity against FLT3 Collection (ATCC; Manassas, VA, USA) and grown in and c-Kit, and on hematopoietic progenitor cells. Potent c- RPMI supplemented with GM-CSF (Invitrogen, Grand Kit inhibitors such as dasatinib, pazopanib, and quizartinib Island, NY, USA). Quizartinib was obtained from Ambit demonstrated the greatest disruption of hematopoietic pro- Biosciences (San Diego, CA, USA). Crenolanib was genitor cells, while sorafenib, which has negligible activity obtained from Arog Pharmaceuticals (Dallas, TX, USA). against c-Kit, demonstrated only minimal disruption. Our Dasatinib, pazopanib, and imatinib were obtained from LC data highlight the importance of determining a therapeutic Laboratories (Woburn, MA, USA). Electrophoresis, index between the targeted receptor and c-Kit for TKIs immunoblotting, and hematopoietic progenitor cell assays used to treat malignancies in order to maintain normal were performed as described.2 Cytokines used included hematopoiesis and improve outcomes. SCF, G-CSF, GM-CSF, IL-3, IL-6, and erythropoietin. Myelosuppression is a common adverse event in new Unused portions of bone marrow from normal donors drug development in oncology. -
Role of Tafazzin in Hematopoiesis and Leukemogenesis
Role of Tafazzin in Hematopoiesis and Leukemogenesis by Ayesh Seneviratne A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Ayesh Seneviratne 2020 Role of Tafazzin in Hematopoiesis and Leukemogenesis Ayesh Seneviratne Doctor of Philosophy Institute of Medical Science University of Toronto 2020 Abstract Tafazzin (TAZ) is a mitochondrial transacylase that remodels the mitochondrial cardiolipin into its mature form. Through a CRISPR screen, we identified TAZ as necessary for the growth and viability of acute myeloid leukemia (AML) cells. Genetic inhibition of TAZ reduced stemness and increased differentiation of AML cells both in vitro and in vivo. In contrast, knockdown of TAZ did not impair normal hematopoiesis under basal conditions. Mechanistically, inhibition of TAZ decreased levels of cardiolipin but also altered global levels of intracellular phospholipids, including phosphatidylserine, which controlled AML stemness and differentiation by modulating toll-like receptor (TLR) signaling (Seneviratne et al., 2019). ii Acknowledgments Firstly, I would like to thank Dr. Aaron Schimmer for his guidance and support during my PhD studies. I really enjoyed our early morning meetings where he provided much needed perspective to navigate the road blocks of my project, whilst continuing to push me. It was a privilege to be mentored by such an excellent clinician scientist. I hope to continue to build on the skills I learned in Dr. Schimmer’s lab as I progress on my path to become a clinician scientist. Working in the Schimmer lab was a wonderful learning environment. I would like to especially thank Dr. -
Clinical Pharmacology of Antiмcancer Agents
A CLINI CLINICAL PHARMACOLOGY OF NTI- C ANTI-CANCER AGENTS C AL PHARMA AN Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren www.esmo.org C ER A This is a user-friendly handbook, designed for young GENTS medical oncologists, where they can access the essential C information they need for providing the treatment which could OLOGY OF have the highest chance of being effective and tolerable. By finding out more about pharmacology from this handbook, young medical oncologists will be better able to assess the different options available and become more knowledgeable in the evaluation of new treatments. ESMO ESMO Handbook Series European Society for Medical Oncology CLINICAL PHARMACOLOGY OF Via Luigi Taddei 4, 6962 Viganello-Lugano, Switzerland Handbook Series ANTI-CANCER AGENTS Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren ESMO Press · ISBN 978-88-906359-1-5 ISBN 978-88-906359-1-5 www.esmo.org 9 788890 635915 ESMO Handbook Series handbook_print_NEW.indd 1 30/08/12 16:32 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS CM15 ESMO Handbook 2012 V14.indd1 1 2/9/12 17:17:35 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS Edited by Cristiana Sessa Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Luca Gianni Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Marina Garassino Oncology Department, Istituto Nazionale dei Tumori, Milan, Italy Henk van Halteren Department of Internal Medicine, Gelderse Vallei Hospital, Ede, The Netherlands ESMO Press CM15 ESMO Handbook 2012 V14.indd3 3 2/9/12 17:17:35 First published in 2012 by ESMO Press © 2012 European Society for Medical Oncology All rights reserved. -
Venetoclax in Combination with Gilteritinib in Patients with Relapsed/Refractory AML
______________________________________________________________________________ Venetoclax in Combination with Gilteritinib in Patients with Relapsed/Refractory AML Naval Daver, MD Associate Professor Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas This is a study that we designed with the AbbVie and Astellas teams as well as lead investigators at other sites in the United States. The study combines two very active drugs in AML, one being a BCL- 2 inhibitor, venetoclax, that is approved in the frontline setting as a combination of azacitidine or low-dose cytarabine with venetoclax for older AML, not suitable for induction; the other is a highly potent selective FLT3 inhibitor that targets both FLT3 ITD and TKD as well as dual mutation and has been approved in the relapsed/refractory setting as a single agent, the drug is called gilteritinib. The approval of gilteritinib was based on a randomized phase 3 study that showed that single-agent gilteritinib was able to produce higher response rates, bone marrow responses, CR/CRh, as well as significantly improved overall survival as compared to standard-of-care high-dose chemotherapy or epigenetic therapy. One of the big questions is, why did we do this combination? Well, one reason is that there is actually very potent preclinical synergy for the FLT3 inhibitors, gilteritinib, but also for quizartinib with venetoclax, and our group has done studies in the lab, as have AbbVie, Astellas, and Genentech teams that support a very high degree of synthetic lethality when you combine next-generation FLT3 inhibitors with the BCL-2 inhibitors such as venetoclax. Also, important to note that one of the major mechanisms of resistance or relapse post-venetoclax is MCL1 upregulation, and the FLT3 inhibitors block MCL1, thereby blocking the escape or relapsed potential by using single-agent venetoclax.