Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia

Menée à partir d'échantillons prélevés sur 50 patients atteints d'une leucémie prolymphocytaire T, cette étude identifie un ensemble de gènes dont les mutations sont associées au développement de la maladie

Résumé en anglais

The comprehensive genetic alterations underlying the pathogenesis of T-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 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 and targeted pharmacological 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.