Universität zu Köln

Kiel, Mark J., Velusamy, Thirunavukkarasu, Rolland, Delphine, Sahasrabuddhe, Anagh A., Chung, Fuzon, Bailey, Nathanael G., Schrader, Alexandra, Li, Bo, Li, Jun Z., Ozel, Ayse B., Betz, Bryan L., Miranda, Roberto N., Medeiros, L. Jeffrey, Zhao, Lili, Herling, Marco, Lim, Megan S. and Elenitoba-Johnson, Kojo S. J. (2014). Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood, 124 (9). S. 1460 - 1473. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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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, andtargeted 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kiel, Mark J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Velusamy, Thirunavukkarasu UNSPECIFIED UNSPECIFIED UNSPECIFIED Rolland, Delphine UNSPECIFIED UNSPECIFIED UNSPECIFIED Sahasrabuddhe, Anagh A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chung, Fuzon UNSPECIFIED UNSPECIFIED UNSPECIFIED Bailey, Nathanael G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schrader, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Bo UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Jun Z. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ozel, Ayse B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Betz, Bryan L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Miranda, Roberto N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Medeiros, L. Jeffrey UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Lili UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Lim, Megan S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Elenitoba-Johnson, Kojo S. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-431803
DOI:	10.1182/blood-2014-03-559542
Journal or Publication Title:	Blood
Volume:	124
Number:	9
Page Range:	S. 1460 - 1473
Date:	2014
Publisher:	AMER SOC HEMATOLOGY
Place of Publication:	WASHINGTON
ISSN:	1528-0020
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SOMATIC MUTATIONS; IN-VITRO; ATM GENE; JAK3; KINASE; STAT5; TRANSLOCATION; DEREGULATION; PROMOTES; MTCP-1 Multiple languages Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43180