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Charles Mullighan

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https://www.readbyqxmd.com/read/27870571/high-frequency-and-poor-outcome-of-philadelphia-chromosome-like-acute-lymphoblastic-leukemia-in-adults
#1
Kathryn G Roberts, Zhaohui Gu, Debbie Payne-Turner, Kelly McCastlain, Richard C Harvey, I-Ming Chen, Deqing Pei, Ilaria Iacobucci, Marcus Valentine, Stanley B Pounds, Lei Shi, Yongjin Li, Jinghui Zhang, Cheng Cheng, Alessandro Rambaldi, Manuela Tosi, Orietta Spinelli, Jerald P Radich, Mark D Minden, Jacob M Rowe, Selina Luger, Mark R Litzow, Martin S Tallman, Peter H Wiernik, Ravi Bhatia, Ibrahim Aldoss, Jessica Kohlschmidt, Krzysztof Mrózek, Guido Marcucci, Clara D Bloomfield, Wendy Stock, Stephen Kornblau, Hagop M Kantarjian, Marina Konopleva, Elisabeth Paietta, Cheryl L Willman, Charles G Mullighan
Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients...
November 21, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27865806/ikaros-exploiting-and-targeting-the-hematopoietic-stem-cell-niche-in-b-progenitor-acute-lymphoblastic-leukemia
#2
REVIEW
Michelle L Churchman, Charles G Mullighan
Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high risk B-progenitor ALL such as BCR-ABL1 positive (Ph+) and Ph-like ALL, and are associated with poor outcome, even in the era of contemporary chemotherapy incorporating tyrosine kinase inhibitors in the treatment of Ph+ ALL. Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiating, skewing lineage of leukemia from myeloid to lymphoid, and in Ph+ leukemia, conferring resistance to TKI therapy without abrogating ABL1 inhibition...
November 16, 2016: Experimental Hematology
https://www.readbyqxmd.com/read/27824051/genomic-analyses-identify-recurrent-mef2d-fusions-in-acute-lymphoblastic-leukaemia
#3
Zhaohui Gu, Michelle Churchman, Kathryn Roberts, Yongjin Li, Yu Liu, Richard C Harvey, Kelly McCastlain, Shalini C Reshmi, Debbie Payne-Turner, Ilaria Iacobucci, Ying Shao, I-Ming Chen, Marcus Valentine, Deqing Pei, Karen L Mungall, Andrew J Mungall, Yussanne Ma, Richard Moore, Marco Marra, Eileen Stonerock, Julie M Gastier-Foster, Meenakshi Devidas, Yunfeng Dai, Brent Wood, Michael Borowitz, Eric E Larsen, Kelly Maloney, Leonard A Mattano, Anne Angiolillo, Wanda L Salzer, Michael J Burke, Francesca Gianni, Orietta Spinelli, Jerald P Radich, Mark D Minden, Anthony V Moorman, Bella Patel, Adele K Fielding, Jacob M Rowe, Selina M Luger, Ravi Bhatia, Ibrahim Aldoss, Stephen J Forman, Jessica Kohlschmidt, Krzysztof Mrózek, Guido Marcucci, Clara D Bloomfield, Wendy Stock, Steven Kornblau, Hagop M Kantarjian, Marina Konopleva, Elisabeth Paietta, Cheryl L Willman, Mignon L Loh, Stephen P Hunger, Charles G Mullighan
Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5...
November 8, 2016: Nature Communications
https://www.readbyqxmd.com/read/27798625/the-genomic-landscape-of-core-binding-factor-acute-myeloid-leukemias
#4
Zachary J Faber, Xiang Chen, Amanda Larson Gedman, Kristy Boggs, Jinjun Cheng, Jing Ma, Ina Radtke, Jyh-Rong Chao, Michael P Walsh, Guangchun Song, Anna K Andersson, Jinjun Dang, Li Dong, Yu Liu, Robert Huether, Zhongling Cai, Heather Mulder, Gang Wu, Michael Edmonson, Michael Rusch, Chunxu Qu, Yongjin Li, Bhavin Vadodaria, Jianmin Wang, Erin Hedlund, Xueyuan Cao, Donald Yergeau, Joy Nakitandwe, Stanley B Pounds, Sheila Shurtleff, Robert S Fulton, Lucinda L Fulton, John Easton, Evan Parganas, Ching-Hon Pui, Jeffrey E Rubnitz, Li Ding, Elaine R Mardis, Richard K Wilson, Tanja A Gruber, Charles G Mullighan, Richard F Schlenk, Peter Paschka, Konstanze Döhner, Hartmut Döhner, Lars Bullinger, Jinghui Zhang, Jeffery M Klco, James R Downing
Acute myeloid leukemia (AML) comprises a heterogeneous group of leukemias frequently defined by recurrent cytogenetic abnormalities, including rearrangements involving the core-binding factor (CBF) transcriptional complex. To better understand the genomic landscape of CBF-AMLs, we analyzed both pediatric (n = 87) and adult (n = 78) samples, including cases with RUNX1-RUNX1T1 (n = 85) or CBFB-MYH11 (n = 80) rearrangements, by whole-genome or whole-exome sequencing. In addition to known mutations in the Ras pathway, we identified recurrent stabilizing mutations in CCND2, suggesting a previously unappreciated cooperating pathway in CBF-AML...
October 31, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27776115/deregulation-of-dux4-and-erg-in-acute-lymphoblastic-leukemia
#5
Jinghui Zhang, Kelly McCastlain, Hiroki Yoshihara, Beisi Xu, Yunchao Chang, Michelle L Churchman, Gang Wu, Yongjin Li, Lei Wei, Ilaria Iacobucci, Yu Liu, Chunxu Qu, Ji Wen, Michael Edmonson, Debbie Payne-Turner, Kerstin B Kaufmann, Shin-Ichiro Takayanagi, Erno Wienholds, Esmé Waanders, Panagiotis Ntziachristos, Sofia Bakogianni, Jingjing Wang, Iannis Aifantis, Kathryn G Roberts, Jing Ma, Guangchun Song, John Easton, Heather L Mulder, Xiang Chen, Scott Newman, Xiaotu Ma, Michael Rusch, Pankaj Gupta, Kristy Boggs, Bhavin Vadodaria, James Dalton, Yanling Liu, Marcus L Valentine, Li Ding, Charles Lu, Robert S Fulton, Lucinda Fulton, Yashodhan Tabib, Kerri Ochoa, Meenakshi Devidas, Deqing Pei, Cheng Cheng, Jun Yang, William E Evans, Mary V Relling, Ching-Hon Pui, Sima Jeha, Richard C Harvey, I-Ming L Chen, Cheryl L Willman, Guido Marcucci, Clara D Bloomfield, Jessica Kohlschmidt, Krzysztof Mrózek, Elisabeth Paietta, Martin S Tallman, Wendy Stock, Matthew C Foster, Janis Racevskis, Jacob M Rowe, Selina Luger, Steven M Kornblau, Sheila A Shurtleff, Susana C Raimondi, Elaine R Mardis, Richard K Wilson, John E Dick, Stephen P Hunger, Mignon L Loh, James R Downing, Charles G Mullighan
Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL). Here we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion...
October 24, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27702824/significance-of-tp53-mutation-in-wilms-tumors-with-diffuse-anaplasia-a-report-from-the-children-s-oncology-group
#6
Ariadne H A G Ooms, Samantha Gadd, Daniela S Gerhard, Malcolm A Smith, Jaime M Guidry Auvil, Daoud Meerzaman, Qing-Rong Chen, Chih Hao Hsu, Chunhua Yan, Cu Nguyen, Ying Hu, Yussanne Ma, Zusheng Zong, Andrew J Mungall, Richard A Moore, Marco A Marra, Vicki Huff, Jeffrey S Dome, Yueh-Yun Chi, Jing Tian, James I Geller, Charles G Mullighan, Jing Ma, David A Wheeler, Oliver A Hampton, Amy L Walz, Marry M van den Heuvel-Eibrink, Ronald R de Krijger, Nicole Ross, Julie M Gastier-Foster, Elizabeth J Perlman
PURPOSE: To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs). EXPERIMENTAL DESIGN: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs. RESULTS: Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [defined as TP53-wild-type (wt)]...
October 4, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27561722/philadelphia-chromosome-like-acute-lymphoblastic-leukemia-in-adults-have-frequent-igh-crlf2-and-jak2-mutations-persistence-of-minimal-residual-disease-and-poor-prognosis
#7
Tobias Herold, Stephanie Schneider, Klaus Metzeler, Martin Neumann, Luise Hartmann, Kathryn G Roberts, Nikola P Konstandin, Philipp A Greif, Kathrin Bräundl, Bianka Ksienzyk, Natalia Huk, Irene Schneider, Evelyn Zellmeier, Vindi Jurinovic, Ulrich Mansmann, Wolfgang Hiddemann, Charles G Mullighan, Stefan K Bohlander, Karsten Spiekermann, Dieter Hölzer, Monika Brüggemann, Claudia D Baldus, Martin Dreyling, Nicola Gökbuget
Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was the genetic and clinical characterization of Ph-like ALL in adults. Twenty-six (13%) of 207 adult B-cell precursor ALL (BCP-ALL) patients (median age: 42 years) were classified as Ph-like using gene expression profiling. The frequency of Ph-like ALL was 27% among 95 BCP-ALL patients negative for BCR-ABL1 and MLL rearrangements...
August 25, 2016: Haematologica
https://www.readbyqxmd.com/read/27311679/comparison-of-genome-sequencing-and-clinical-genotyping-for-pharmacogenes
#8
W Yang, G Wu, U Broeckel, C A Smith, V Turner, C E Haidar, S Wang, R Carter, S E Karol, G Neale, K R Crews, J J Yang, C G Mullighan, J R Downing, W E Evans, M V Relling
We compared whole exome sequencing (WES, n = 176 patients) and whole genome sequencing (WGS, n = 68) and clinical genotyping (DMET array-based approach) for interrogating 13 genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. We focused on 127 CPIC important variants: 103 single nucleotide variations (SNV), 21 insertion/deletions (Indel), HLA-B alleles, and two CYP2D6 structural variations. WES and WGS provided interrogation of nonoverlapping sets of 115 SNV/Indels with call rate >98%...
October 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27249738/advances-in-the-genetics-and-therapy-of-acute-lymphoblastic-leukemia
#9
Sabina Chiaretti, Valentina Gianfelici, Susan M O'Brien, Charles G Mullighan
Acute lymphoblastic leukemia (ALL) remains an important cause of morbidity in children and adults. In this article, we highlight advances in the genetics and therapy of three key subtypes of ALL: T-cell ALL, BCR-ABL1 (Philadelphia [Ph] chromosone-positive), and Ph-like ALL. T-ALL is an aggressive disease that accounts for about 15% and 25% of ALL among pediatric and adult cohorts, respectively, and exhibits a multistep nature of cancer initiation and progression. The integration of cytogenetics, molecular biology, and immunophenotype analyses has led to the identification of defined T-ALL subgroups, such as early T-cell precursor ALL and novel lesions with a prognostic role, for which specific inhibitors are being developed...
2016: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/27229714/characterization-of-leukemias-with-etv6-abl1-fusion
#10
Marketa Zaliova, Anthony V Moorman, Giovanni Cazzaniga, Martin Stanulla, Richard C Harvey, Kathryn G Roberts, Sue L Heatley, Mignon L Loh, Marina Konopleva, I-Ming Chen, Olga Zimmermannova, Claire Schwab, Owen Smith, Marie-Joelle Mozziconacci, Christian Chabannon, Myungshin Kim, J H Frederik Falkenburg, Alice Norton, Karen Marshall, Oskar A Haas, Julia Starkova, Jan Stuchly, Stephen P Hunger, Deborah White, Charles G Mullighan, Cheryl L Willman, Jan Stary, Jan Trka, Jan Zuna
To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing...
September 2016: Haematologica
https://www.readbyqxmd.com/read/27123491/synergism-of-fak-and-tyrosine-kinase-inhibition-in-ph-b-all
#11
Michelle L Churchman, Kathryn Evans, Jennifer Richmond, Alissa Robbins, Luke Jones, Irina M Shapiro, Jonathan A Pachter, David T Weaver, Peter J Houghton, Malcolm A Smith, Richard B Lock, Charles G Mullighan
BCR-ABL1(+) B progenitor acute lymphoblastic leukemia (Ph(+) B-ALL) is an aggressive disease that frequently responds poorly to currently available therapies. Alterations in IKZF1, which encodes the lymphoid transcription factor Ikaros, are present in over 80% of Ph(+) ALL and are associated with a stem cell-like phenotype, aberrant adhesion molecule expression and signaling, leukemic cell adhesion to the bone marrow stem cell niche, and poor outcome. Here, we show that FAK1 is upregulated in Ph(+) B-ALL with further overexpression in IKZF1-altered cells and that the FAK inhibitor VS-4718 potently inhibits aberrant FAK signaling and leukemic cell adhesion, potentiating responsiveness to tyrosine kinase inhibitors, inducing cure in vivo...
2016: JCI Insight
https://www.readbyqxmd.com/read/27053534/welcoming-a-new-age-for-gene-therapy-in-hematology
#12
Mitchell J Weiss, Charles G Mullighan
Our capacities to understand and manipulate mammalian genomes are accelerating at an astounding pace. In 2007, Capecchi, Evans, and Smithies were awarded the Nobel Prize in medicine for their work on gene targeting, which showed that embryonic stem cells could be modified by homologous recombination (HR) with engineered template DNA to alter virtually any gene and create mutant mice. This work revolutionized biology by allowing investigators to study the in vivo consequences of selected gene alteration. However, the efficiency of HR in embryonic stem cells is unpredictable, depending on the target gene and HR template...
May 26, 2016: Blood
https://www.readbyqxmd.com/read/26966091/integrated-genomic-dna-rna-profiling-of-hematologic-malignancies-in-the-clinical-setting
#13
Jie He, Omar Abdel-Wahab, Michelle K Nahas, Kai Wang, Raajit K Rampal, Andrew M Intlekofer, Jay Patel, Andrei Krivstov, Garrett M Frampton, Lauren E Young, Shan Zhong, Mark Bailey, Jared R White, Steven Roels, Jason Deffenbaugh, Alex Fichtenholtz, Timothy Brennan, Mark Rosenzweig, Kimberly Pelak, Kristina M Knapp, Kristina W Brennan, Amy L Donahue, Geneva Young, Lazaro Garcia, Selmira T Beckstrom, Mandy Zhao, Emily White, Vera Banning, Jamie Buell, Kiel Iwanik, Jeffrey S Ross, Deborah Morosini, Anas Younes, Alan M Hanash, Elisabeth Paietta, Kathryn Roberts, Charles Mullighan, Ahmet Dogan, Scott A Armstrong, Tariq Mughal, Jo-Anne Vergilio, Elaine Labrecque, Rachel Erlich, Christine Vietz, Roman Yelensky, Philip J Stephens, Vincent A Miller, Marcel R M van den Brink, Geoff A Otto, Doron Lipson, Ross L Levine
The spectrum of somatic alterations in hematologic malignancies includes substitutions, insertions/deletions (indels), copy number alterations (CNAs), and a wide range of gene fusions; no current clinically available single assay captures the different types of alterations. We developed a novel next-generation sequencing-based assay to identify all classes of genomic alterations using archived formalin-fixed paraffin-embedded blood and bone marrow samples with high accuracy in a clinically relevant time frame, which is performed in our Clinical Laboratory Improvement Amendments-certified College of American Pathologists-accredited laboratory...
June 16, 2016: Blood
https://www.readbyqxmd.com/read/26892479/clinical-impact-of-abl1-kinase-domain-mutations-and-ikzf1-deletion-in-adults-under-age-60-with-philadelphia-chromosome-positive-ph-acute-lymphoblastic-leukemia-all-molecular-analysis-of-calgb-alliance-10001-and-9665
#14
Rebecca DeBoer, Gregory Koval, Flora Mulkey, Meir Wetzler, Steven Devine, Guido Marcucci, Richard M Stone, Richard A Larson, Clara D Bloomfield, Susan Geyer, Charles G Mullighan, Wendy Stock
Recent studies have identified oncogenic lesions in Philadelphia chromosome-positive (Ph+)  acute lymphoblastic leukemia (ALL) and ABL1 kinase mutations that confer resistance to tyrosine kinase inhibitors. We sought to determine the prevalence and clinical impact of these lesions in patients on CALGB 10001, a previously reported Phase II study of imatinib, chemotherapy, and hematopoietic cell transplant in adult Ph + ALL. Of the 58 enrolled, 22 relapsed. By direct sequencing, an ABL1 kinase mutation known to induce imatinib resistance was present at relapse in 13 of 20...
October 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/26859458/truncating-erythropoietin-receptor-rearrangements-in-acute-lymphoblastic-leukemia
#15
Ilaria Iacobucci, Yongjin Li, Kathryn G Roberts, Stephanie M Dobson, Jaeseung C Kim, Debbie Payne-Turner, Richard C Harvey, Marcus Valentine, Kelly McCastlain, John Easton, Donald Yergeau, Laura J Janke, Ying Shao, I-Ming L Chen, Michael Rusch, Sasan Zandi, Steven M Kornblau, Marina Konopleva, Elias Jabbour, Elisabeth M Paietta, Jacob M Rowe, Ching-Hon Pui, Julie Gastier-Foster, Zhaohui Gu, Shalini Reshmi, Mignon L Loh, Janis Racevskis, Martin S Tallman, Peter H Wiernik, Mark R Litzow, Cheryl L Willman, John D McPherson, James R Downing, Jinghui Zhang, John E Dick, Stephen P Hunger, Charles G Mullighan
Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues...
February 8, 2016: Cancer Cell
https://www.readbyqxmd.com/read/26635203/mllt1-yeats-domain-mutations-in-clinically-distinctive-favourable-histology-wilms-tumours
#16
Elizabeth J Perlman, Samantha Gadd, Stefan T Arold, Anand Radhakrishnan, Daniela S Gerhard, Lawrence Jennings, Vicki Huff, Jaime M Guidry Auvil, Tanja M Davidsen, Jeffrey S Dome, Daoud Meerzaman, Chih Hao Hsu, Cu Nguyen, James Anderson, Yussanne Ma, Andrew J Mungall, Richard A Moore, Marco A Marra, Charles G Mullighan, Jing Ma, David A Wheeler, Oliver A Hampton, Julie M Gastier-Foster, Nicole Ross, Malcolm A Smith
Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation...
December 4, 2015: Nature Communications
https://www.readbyqxmd.com/read/26522332/germline-genetic-variation-in-etv6-and-risk-of-childhood-acute-lymphoblastic-leukaemia-a-systematic-genetic-study
#17
Takaya Moriyama, Monika L Metzger, Gang Wu, Rina Nishii, Maoxiang Qian, Meenakshi Devidas, Wenjian Yang, Cheng Cheng, Xueyuan Cao, Emily Quinn, Susana Raimondi, Julie M Gastier-Foster, Elizabeth Raetz, Eric Larsen, Paul L Martin, W Paul Bowman, Naomi Winick, Yoshihiro Komada, Shuoguo Wang, Michael Edmonson, Heng Xu, Elaine Mardis, Robert Fulton, Ching-Hon Pui, Charles Mullighan, William E Evans, Jinghui Zhang, Stephen P Hunger, Mary V Relling, Kim E Nichols, Mignon L Loh, Jun J Yang
BACKGROUND: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL...
December 2015: Lancet Oncology
https://www.readbyqxmd.com/read/26465987/acute-lymphoblastic-leukemia-in-children
#18
REVIEW
Stephen P Hunger, Charles G Mullighan
No abstract text is available yet for this article.
October 15, 2015: New England Journal of Medicine
https://www.readbyqxmd.com/read/26443624/tumor-specific-hsp90-inhibition-as-a-therapeutic-approach-in-jak-mutant-acute-lymphoblastic-leukemias
#19
MULTICENTER STUDY
Nicole Kucine, Sachie Marubayashi, Neha Bhagwat, Efthymia Papalexi, Priya Koppikar, Marta Sanchez Martin, Lauren Dong, Marty S Tallman, Elisabeth Paietta, Kai Wang, Jie He, Doron Lipson, Phil Stephens, Vince Miller, Jacob M Rowe, Julie Teruya-Feldstein, Charles G Mullighan, Adolfo A Ferrando, Andrei Krivtsov, Scott Armstrong, Laura Leung, Stefan O Ochiana, Gabriela Chiosis, Ross L Levine, Maria Kleppe
The development of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myeloproliferative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mutated acute lymphoblastic leukemia (ALL). However, the limited ability of JAK inhibition to induce molecular or clinicopathological responses in MPNs suggests a need for development of better therapies for JAK kinase-dependent malignancies. Here, we demonstrate that heat shock protein 90 (HSP90) inhibition using a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome persistence to JAK-inhibitor therapy in ALL cells...
November 26, 2015: Blood
https://www.readbyqxmd.com/read/26321221/efficacy-of-retinoids-in-ikzf1-mutated-bcr-abl1-acute-lymphoblastic-leukemia
#20
Michelle L Churchman, Jonathan Low, Chunxu Qu, Elisabeth M Paietta, Lawryn H Kasper, Yunchao Chang, Debbie Payne-Turner, Mark J Althoff, Guangchun Song, Shann-Ching Chen, Jing Ma, Michael Rusch, Dan McGoldrick, Michael Edmonson, Pankaj Gupta, Yong-Dong Wang, William Caufield, Burgess Freeman, Lie Li, John C Panetta, Sharyn Baker, Yung-Li Yang, Kathryn G Roberts, Kelly McCastlain, Ilaria Iacobucci, Jennifer L Peters, Victoria E Centonze, Faiyaz Notta, Stephanie M Dobson, Sasan Zandi, John E Dick, Laura Janke, Junmin Peng, Kiran Kodali, Vishwajeeth Pagala, Jaeki Min, Anand Mayasundari, Richard T Williams, Cheryl L Willman, Jacob Rowe, Selina Luger, Ross A Dickins, R Kiplin Guy, Taosheng Chen, Charles G Mullighan
Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high-risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here, we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest, and attenuation of proliferation without direct cytotoxicity...
September 14, 2015: Cancer Cell
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