Universität zu Köln

Wahnschaffe, Linus, Braun, Till, Timonen, Sanna ORCID: 0000-0002-8139-5950, Giri, Anil K., Schrader, Alexandra, Wagle, Prerana, Almusa, Henrikki, Johansson, Patricia, Bellanger, Dorine, Lopez, Cristina ORCID: 0000-0001-6644-1659, Haferlach, Claudia, Stern, Marc-Henri ORCID: 0000-0002-8100-2272, Duerig, Jan, Siebert, Reiner, Mustjoki, Satu ORCID: 0000-0002-0816-8241, Aittokallio, Tero ORCID: 0000-0002-0886-9769 and Herling, Marco (2019). JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL. Cancers, 11 (12). BASEL: MDPI. ISSN 2072-6694

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Abstract

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell leukemia. Recent studies detected genomic aberrations affecting JAK and STAT genes in T-PLL. Due to the limited number of primary patient samples available, genomic analyses of the JAK/STAT pathway have been performed in rather small cohorts. Therefore, we conducted-via a primary-data based pipeline-a meta-analysis that re-evaluated the genomic landscape of T-PLL. It included all available data sets with sequence information on JAK or STAT gene loci in 275 T-PLL. We eliminated overlapping cases and determined a cumulative rate of 62.1% of cases with mutated JAK or STAT genes. Most frequently, JAK1 (6.3%), JAK3 (36.4%), and STAT5B (18.8%) carried somatic single-nucleotide variants (SNVs), with missense mutations in the SH2 or pseudokinase domains as most prevalent. Importantly, these lesions were predominantly subclonal. We did not detect any strong association between mutations of a JAK or STAT gene with clinical characteristics. Irrespective of the presence of gain-of-function (GOF) SNVs, basal phosphorylation of STAT5B was elevated in all analyzed T-PLL. Fittingly, a significant proportion of genes encoding for potential negative regulators of STAT5B showed genomic losses (in 71.4% of T-PLL in total, in 68.4% of T-PLL without any JAK or STAT mutations). They included DUSP4, CD45, TCPTP, SHP1, SOCS1, SOCS3, and HDAC9. Overall, considering such losses of negative regulators and the GOF mutations in JAK and STAT genes, a total of 89.8% of T-PLL revealed a genomic aberration potentially explaining enhanced STAT5B activity. In essence, we present a comprehensive meta-analysis on the highly prevalent genomic lesions that affect genes encoding JAK/STAT signaling components. This provides an overview of possible modes of activation of this pathway in a large cohort of T-PLL. In light of new advances in JAK/STAT inhibitor development, we also outline translational contexts for harnessing active JAK/STAT signaling, which has emerged as a 'secondary' hallmark of T-PLL.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wahnschaffe, Linus UNSPECIFIED UNSPECIFIED UNSPECIFIED Braun, Till UNSPECIFIED UNSPECIFIED UNSPECIFIED Timonen, Sanna UNSPECIFIED orcid.org/0000-0002-8139-5950 UNSPECIFIED Giri, Anil K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schrader, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagle, Prerana UNSPECIFIED UNSPECIFIED UNSPECIFIED Almusa, Henrikki UNSPECIFIED UNSPECIFIED UNSPECIFIED Johansson, Patricia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bellanger, Dorine UNSPECIFIED UNSPECIFIED UNSPECIFIED Lopez, Cristina UNSPECIFIED orcid.org/0000-0001-6644-1659 UNSPECIFIED Haferlach, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Stern, Marc-Henri UNSPECIFIED orcid.org/0000-0002-8100-2272 UNSPECIFIED Duerig, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Siebert, Reiner UNSPECIFIED UNSPECIFIED UNSPECIFIED Mustjoki, Satu UNSPECIFIED orcid.org/0000-0002-0816-8241 UNSPECIFIED Aittokallio, Tero UNSPECIFIED orcid.org/0000-0002-0886-9769 UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-125428
DOI:	10.3390/cancers11121833
Journal or Publication Title:	Cancers
Volume:	11
Number:	12
Date:	2019
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELL PROLYMPHOCYTIC LEUKEMIA; JAK-STAT PATHWAY; MUTATIONS; REVEALS Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12542