TY - JOUR
T1 - Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia
AU - Kiel, Mark J.
AU - Velusamy, Thirunavukkarasu
AU - Rolland, Delphine
AU - Sahasrabuddhe, Anagh A.
AU - Chung, Fuzon
AU - Bailey, Nathanael G.
AU - Schrader, Alexandra
AU - Li, Bo
AU - Li, Jun Z.
AU - Ozel, Ayse B.
AU - Betz, Bryan L.
AU - Miranda, Roberto N.
AU - Medeiros, L. Jeffrey
AU - Zhao, Lili
AU - Herling, Marco
AU - Lim, Megan S.
AU - Elenitoba-Johnson, Kojo S.J.
PY - 2014/8/28
Y1 - 2014/8/28
N2 - The comprehensive genetic alterations underlying the pathogenesis of T-cell prolym-phocytic 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,andtargeted pharmacologic inhibition ofSTAT5with 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.
AB - The comprehensive genetic alterations underlying the pathogenesis of T-cell prolym-phocytic 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,andtargeted pharmacologic inhibition ofSTAT5with 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.
UR - http://www.scopus.com/inward/record.url?scp=84907317719&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907317719&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-03-559542
DO - 10.1182/blood-2014-03-559542
M3 - Article
C2 - 24825865
AN - SCOPUS:84907317719
SN - 0006-4971
VL - 124
SP - 1460
EP - 1472
JO - Blood
JF - Blood
IS - 9
ER -