Indexed in

License and use

Citations

Cited 33 times in

Cited 24 times in

Cited 41 times in

Altmetrics

Grant support

This research was funded by the DFG Research Unit FOR1961 (Control-T; HE3553/4-2) and the DFG CRC SFB 1076 (Project B9), by the Koln Fortune program, by the Fritz Thyssen Foundation (10.15.2.034MN), by the Academy of Finland (grants 292611,295504, 310507, 326238), and by the Cancer Society of Finland. This work was also supported by the EU Transcan-2 consortium 'ERANET-PLL' and by the ERAPerMed consortium 'JAKSTAT-TARGET'. A.S. is funded by a scholarship through the Jose Carreras Leukemia Foundation (DJCLS 03 F/2016).

Analysis of institutional authors

Share

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

Publicated to:Cancers. 11 (12): 1833- - 2019-12-01 11(12), DOI: 10.3390/cancers11121833

Authors: Wahnschaffe, Linus; Braun, Till; Timonen, Sanna; Giri, Anil K.; Schrader, Alexandra; Wagle, Prerana; Almusa, Henrikki; Johansson, Patricia; Bellanger, Dorine; Lopez, Cristina; Haferlach, Claudia; Stern, Marc-Henri; Duerig, Jan; Siebert, Reiner; Mustjoki, Satu; Aittokallio, Tero; Herling, Marco;

Affiliations

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.

Keywords