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

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.

Targeting STAT3 and STAT5 in Cancer

“…Phospho-STAT5 was shown to play a key role in CD34+/CD38− myeloproliferative neoplasms with downregulation by pharmacologic inhibition of JAK and STAT [24]. JAK/STAT mutations were also identified in patients with the rare and aggressive T-cell prolymphocytic leukemia (T-PLL), pointing towards a possible mode of transformation [25]. Additionally, STAT3 (and not STAT5B) mutations were identified in multiple peripheral T-cell lymphomas (PTCL), as well as high pY-STAT3 expression, particularly in angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) patient samples, two different PTCL cancer types [26].…”

Micro-RNA networks in T-cell prolymphocytic leukemia reflect T-cell activation and shape DNA damage response and survival pathways

“…1,11 Activating lesions in janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules as well as epigenetic aberrations have emerged as further hallmarks of T-PLL pathology, resulting in a sustained survival signaling and pro-oncogenic cell cycle deregulation. 1,[12][13][14][15] Despite these recent advances, a better understanding of T-PLL pathobiology is of importance in order to identify novel treatment options.…”

First reported case of BRAF V600E mutation in T‐cell prolymphocytic leukaemia

“…In this paper, we report the first known BRAF V600E mutation found in T‐PLL. Previous studies have shown recurrent mutations in the JAK/STAT pathway, ATM , genetic modifiers and DNA repair mechanisms; this BRAF V600E mutation likely represents an uncommon finding but more studies are required to identify other such mutations with potential therapeutic benefit 10‐15 . Our patient, having progressed through standard of care treatments, was trialled on novel treatments including dasatinib, venetoclax and vemurafenib.…”