Genes encoding members of the JAK‐STAT pathway or epigenetic regulators are recurrently mutated in T‐cell prolymphocytic leukaemia

Abstract

T-cell prolymphocytic leukaemia (T-PLL) is an aggressive leukaemia. The primary genetic alteration in T-PLL are the inv(14)(q11q32)/t(14;14)(q11;q32) leading to TRD/TRA-TCL1A fusion, or the t(X;14)(q28;q11) associated with TRD/TRA-MTCP1 fusion. However, additional cooperating abnormalities are necessary for emergence of the full neoplastic phenotype. Though the pattern of secondary chromosomal aberrations is remarkably conserved, targets of the changes are largely unknown. We analysed a cohort of 43 well-characterized T-PLL for hotspot mutations in the genes JAK3, STAT5B and RHOA. Additionally, we selected a subset of 23 T-PLL cases for mutational screening of 54 genes known to be recurrently mutated in T-cell and other haematological neoplasms. Activating mutations in the investigated regions of the JAK3 and STAT5B genes were detected in 30% (13/43) and 21% (8/39) of the cases, respectively, and were mutually exclusive. Further, we identified mutations in the genes encoding the epigenetic regulators EZH2 in 13% (3/23), TET2 in 17% (4/23) and BCOR in 9% (2/23) of the cases. We confirmed that the JAK-STAT pathway is a major mutational target, and identified epigenetic regulators recurrently mutated in T-PLL. These findings complement the mutational spectrum of secondary aberrations in T-PLL and underscore the potential therapeutical relevance of epigenetic regulators in T-PLL.

Prognostic significance of cytogenetic abnormalities in T‐cell prolymphocytic leukemia

“…A second critical mutation then imparts one of the malignant T-cells with a prominent survival/proliferative advantage leading to an aggressive phase of disease in which tumor burden grows rapidly, such as the activating mutations of the IL2RG-JAK1-JAK3-STAT5B. 28,29 This model fits well with the much better OS observed in patients with a NK and suggests that patients with NK could be at the "first hit" indolent stage whereas those patients with a CK likely have progressed to a more aggressive "second hit" disease stage. Genetic mutations such as TP53, extra copy number of MYC as well as JAK3…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…IFNG and STAT1) and upregulated IL-12 target genes [109]. In addition, mutations in epigenetic regulators catalyzing methylation and acetylation changes such as EZH2, TET2 , and BCOR were found in a number of T-PLL patients [76]. …”

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

“…The second most common lesions are genomic alterations of the tumor suppressor ataxia telangiectasia mutated (ATM), found in >85% of cases [9]. In addition to these lesions, activating mutations targeting the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway components were identified in these series of genomic analyses [9][10][11][12][13][14][15][16][17][18].…”

“…Constitutively active JAK/STAT signaling induces T-cell tumors in mice [22,23]. Using different sequencing approaches, activating mutations of JAK1, JAK3, and STAT5B were identified as the most recurrent genomic aberrations affecting JAK/STAT genes in T-PLL [9][10][11][12][13][14][15][16][17][18]. However, prevalence of gene mutations, information on their allele frequencies, assessment of negative regulators of JAK/STAT signaling, and the phosphorylation status of the most recurrently affected JAK/STAT proteins vary considerably or are not reported in these studies [9][10][11][12][13][14][15][16][17][18].…”