Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia

MJ Kiel, T Velusamy, D Rolland… - Blood, The Journal …, 2014 - ashpublications.org
MJ Kiel, T Velusamy, D Rolland, AA Sahasrabuddhe, F Chung, NG Bailey, A Schrader, B Li
Blood, The Journal of the American Society of Hematology, 2014ashpublications.org
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 …
Abstract
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.
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