Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia

Abstract

Aggressive NK-cell leukemia (ANKL) is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% (14/29) of ANKL patients, while the extracellular STAT3 stimulator IL10 was elevated by an average of 56-fold (P < 0.0001) in the plasma of all patients examined. Additional frequently mutated genes included TP53 (34%), TET2 (28%), CREBBP (21%) and MLL2 (21%). Patient NK leukemia cells showed prominent activation of STAT3 phosphorylation, MYC expression and transcriptional activities in multiple metabolic pathways. Functionally, STAT3 activation and MYC expression were critical for the proliferation and survival of ANKL cells. STAT signaling regulated the MYC transcription program, and both STAT signaling and MYC transcription were required to maintain the activation of nucleotide synthesis and glycolysis. Collectively, the JAK-STAT pathway represents a major target for genomic alterations and IL10 stimulation in ANKL. This newly discovered JAK/STAT-MYC-biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia.

Aggressive NK-Cell Leukemia

“…In approximately half of the cases, mutations in epigenetic regulatory molecules and or histone modification molecules were also detected, including four cases with DDX3X , an RNA helicase. Huang et al analyzed 8 patients with ANKL by whole-genome sequencing and 29 patients by target sequencing ( 24 ). The mean number of non-synonymous mutations was 40.…”

Aggressive NK Cell Leukemia: Current State of the Art

“…The advent of next generation sequencing methods has provided an unprecedented impetus for understanding the molecular pathogenesis of ANKL. Three recent studies [ 19 , 62 , 63 ] provided a comprehensive genetic analysis of ANKL via next generation sequencing ( Table 3 ). While the findings in these studies show some differences that are likely the result of differing methodologies, they share many common threads that provide insight into the molecular landscape of ANKL.…”

“…They showed frequent genetic mutations in the JAK/STAT (21% of cases exhibited STAT3 mutations) and RAS-MAPK signaling pathways [ 62 ]. Similarly, Huang et al analyzed eight patients with ANKL by whole-genome sequencing (WGS) and 29 ANKL (including the eight patients analyzed by WGS) patients by targeted sequencing [ 63 ]. They noted that mutations in molecules of the JAK/STAT system, namely, STAT3 , STAT5B , STAT5A , JAK2 , JAK3 , STAT6 , SOCS1 , SOCS3 , and PTPN11 , were seen in 48% of patients, with 17% of the cases harboring STAT3 mutations [ 63 ].…”

“…Similarly, Huang et al analyzed eight patients with ANKL by whole-genome sequencing (WGS) and 29 ANKL (including the eight patients analyzed by WGS) patients by targeted sequencing [ 63 ]. They noted that mutations in molecules of the JAK/STAT system, namely, STAT3 , STAT5B , STAT5A , JAK2 , JAK3 , STAT6 , SOCS1 , SOCS3 , and PTPN11 , were seen in 48% of patients, with 17% of the cases harboring STAT3 mutations [ 63 ]. El Hussein et al analyzed six ANKL patients, finding mutations in JAK1 in one patient (who also harbored a mutation in STAT3), JAK3 in one patient, and STAT3 in three patients [ 19 ].…”

“…Huang et al [ 63 ] and Dufva et al [ 62 ] found that most of the STAT3 and STAT5B mutations were localized to exons 20 and 21 encoding the Src homology 2 (SH2) domain, which mediates STAT protein dimerization [ 63 ]. This domain also constitutes the hotspot containing activating mutations in NKTCL [ 55 , 61 ].…”