Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia.
The comprehensive genetic alterations underlying the pathogenesis of T-cell prolymphocytic leukemia (T-PLL) are unknown. To address this, we performed whole-genome sequencing (WGS), whole-exome sequencing (WES), high-resolution copy-number analysis, and Sanger resequencing of a large cohort of T-PLL. WGS and WES identified novel mutations in recurrently altered genes not previously implicated in T-PLL including EZH2, FBXW10, and CHEK2. Strikingly, WGS and/or WES showed largely mutually exclusive mutations affecting IL2RG, JAK1, JAK3, or STAT5B in 38 of 50 T-PLL genomes (76.0%). Notably, gain-of-function IL2RG mutations are novel and have not been reported in any form of cancer. Further, high-frequency mutations in STAT5B have not been previously reported in T-PLL. Functionally, IL2RG-JAK1-JAK3-STAT5B mutations led to signal transducer and activator of transcription 5 (STAT5) hyperactivation, transformed Ba/F3 cells resulting in cytokine-independent growth, and/or enhanced colony formation in Jurkat T cells. Importantly, primary T-PLL cells exhibited constitutive activation of STAT5, and targeted pharmacologic inhibition of STAT5 with pimozide induced apoptosis in primary T-PLL cells. These results for the first time provide a portrait of the mutational landscape of T-PLL and implicate deregulation of DNA repair and epigenetic modulators as well as high-frequency mutational activation of the IL2RG-JAK1-JAK3-STAT5B axis in the pathogenesis of T-PLL. These findings offer opportunities for novel targeted therapies in this aggressive leukemia.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
Mark J
MJ
Kiel
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
Thirunavukkarasu
T
Velusamy
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
Delphine
D
Rolland
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
Anagh A
AA
Sahasrabuddhe
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
Fuzon
F
Chung
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
Nathanael G
NG
Bailey
Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Medicine, University of Cologne, Cologne, Germany;
Alexandra
A
Schrader
Department of Computational Medicine and Bioinformatics and.
Bo
B
Li
Department of Computational Medicine and Bioinformatics and Department of Human Genetics, University of Michigan, Ann Arbor, MI;
Jun Z
JZ
Li
Department of Human Genetics, University of Michigan, Ann Arbor, MI;
Ayse B
AB
Ozel
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
Bryan L
BL
Betz
The University of Texas MD Anderson Cancer Center, Houston, TX; and.
Roberto N
RN
Miranda
The University of Texas MD Anderson Cancer Center, Houston, TX; and.
L Jeffrey
LJ
Medeiros
Department of Biostatistics, University of Michigan Medical School, Ann Arbor, MI.
Lili
L
Zhao
Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Medicine, University of Cologne, Cologne, Germany;
Marco
M
Herling
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
Megan S
MS
Lim
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
Kojo S J
KS
Elenitoba-Johnson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D015331:Cohort Studies; D003198:Computer Simulation; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D059472:Exome; D005260:Female; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D053613:Janus Kinase 1 / Q000235:genetics; D053616:Janus Kinase 3 / Q000737:chemistry / Q000235:genetics; D015461:Leukemia, Prolymphocytic, T-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010868:Pimozide / Q000494:pharmacology; D011487:Protein Conformation; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D010868:Pimozide; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins