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Comprehensive Mutational Analysis of Primary and Relapse Acute Promyelocytic Leukemia. (Leukemia, Apr 2016)

Madan V1, Shyamsunder P1, Han L1,2, Mayakonda A1, Nagata Y3, Sundaresan J1, Kanojia D1, Yoshida K3, Ganesan S4, Hattori N1, Fulton N5, Tan KT1, Alpermann T6, Kuo MC7, Rostami S8, Matthews J9, Sanada M3, Liu LZ1, Shiraishi Y10, Miyano S10, Chendamarai E4, Hou HA11, Malnassy G5, Ma T12, Garg M1, Ding LW1, Sun QY1, Chien W1, Ikezoe T13, Lill M14, Biondi A15, Larson RA16, Powell BL17, Lübbert M12, Chng WJ1,2,18, Tien HF11, Heuser M19, Ganser A19, Koren-Michowitz M20,21, Kornblau SM9, Kantarjian HM9, Nowak D22, Hofmann WK22, Yang H1, Stock W5, Ghavamzadeh A8, Alimoghaddam K8, Haferlach T6, Ogawa S3, Shih LY7, Mathews V4, Koeffler HP1,14,18

1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
3Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
4Department of Haematology, Christian Medical College, Vellore, India.
5Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
6Munich Leukemia Laboratory (MLL), Munich, Germany.
7Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
8Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
9Section of Molecular Hematology & Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
10Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
11Department of Internal Medicine, National Taiwan University, Medical College and Hospital, Taipei, Taiwan.
12Division of Hematology, Oncology and Stem Cell Transplantation, Department of Internal Medicine, University of Freiburg Medical Center, Freiburg, Germany.
13Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
14Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, USA.
15Paediatric Haematology-Oncology Department and ‘Tettamanti’ Research Centre, Milano-Bicocca University, ‘Fondazione MBBM’, San Gerardo Hospital, Monza, Italy.
16Department of Medicine, University of Chicago Comprehensive Cancer Center, Chicago, IL, USA.
17Department of Internal Medicine, Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA.
18Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), Singapore.
19Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
20Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
21Division of Hematology and Bone Marrow Transplantation, Sheba Medical Center, Tel Hashomer, Israel.
22Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.


Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17) leading to formation of PML-RARA fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, while mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large scale activation of gene expression and reduced in vitro differentiation potential.

PMID: 27063598