Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia
Journal
Leukemia
Journal Volume
30
Journal Issue
8
Pages
1672-1681
Date Issued
2016
Author(s)
Madan V.
Shyamsunder P.
Han L.
Mayakonda A.
Nagata Y.
Sundaresan J.
Kanojia D.
Yoshida K.
Ganesan S.
Hattori N.
Fulton N.
Tan K.-T.
Alpermann T.
Kuo M.-C.
Rostami S.
Matthews J.
Sanada M.
Liu L.-Z.
Shiraishi Y.
Miyano S.
Chendamarai E.
Malnassy G.
Ma T.
Garg M.
Ding L.-W.
Sun Q.-Y.
Chien W.
Ikezoe T.
Lill M.
Biondi A.
Larson R.A.
Powell B.L.
Lübbert M.
Chng W.J.
Heuser M.
Ganser A.
Koren-Michowitz M.
Kornblau S.M.
Kantarjian H.M.
Nowak D.
Hofmann W.-K.
Yang H.
Stock W.
Ghavamzadeh A.
Alimoghaddam K.
Haferlach T.
Ogawa S.
Shih L.-Y.
Mathews V.
Koeffler H.P.
Abstract
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 the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) 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, whereas 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. ? 2016 Macmillan Publishers Limited.
SDGs
Other Subjects
arid1a protein; arid1b protein; bpi protein; Flt3 ligand; hoxc4 protein; ikzf2 protein; interferon regulatory factor 5; K ras protein; n ras protein; nfe2 protein; prg2 protein; promyelocytic leukemia protein; protein; prtn3 protein; rara protein; short hairpin RNA; transcription factor ETV6; transcription factor EZH2; transcription factor GATA 1; transcription factor GATA 2; transcription factor RUNX1; unclassified drug; Wnt7b protein; WT1 protein; ARID1A protein, human; ARID1B protein, human; DNA binding protein; nuclear protein; transcription factor; adolescent; adult; aged; Article; bioinformatics; cell differentiation; child; down regulation; exome; female; frameshift mutation; gene expression; gene silencing; human; incidence; indel mutation; leukemia relapse; ligand binding; loss of function mutation; major clinical study; male; missense mutation; mutational analysis; myeloid leukemia cell line; nonsense mutation; pathogenesis; point mutation; primary tumor; priority journal; promyelocytic leukemia; RNA sequence; sequence analysis; signal transduction; somatic mutation; subsequent targeted sequencing; upregulation; whole exome sequencing; wild type; dna mutational analysis; gene expression profiling; genetics; procedures; promyelocytic leukemia; recurrent disease; Cell Differentiation; DNA Mutational Analysis; DNA-Binding Proteins; Exome; Gene Expression Profiling; Humans; Leukemia, Promyelocytic, Acute; Nuclear Proteins; Recurrence; Transcription Factors
Publisher
Nature Publishing Group
Type
journal article