Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target

Abstract

Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies.

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

“…3b). TET2 alterations were associated with development of myeloid 38 and lymphoid 39 malignancies, and a TET2 truncating variant was observed in one ANKL case 11 . The validated loss-of-function TET2 truncating variant was associated with a particularly high mutation burden in patient #165.…”

“…Evidence on the genomic landscape of T-LGLL pointed to a key role of somatic mutations within JAK/STAT (mostly in STAT3 and STAT5B genes) and Ras/MAPK pathways [3][4][5][6][7][8][9][10] . In ANKL and NKTCL, JAK2 and STAT3 mutations, lesions of epigenetic modifiers and tumor suppressors were detected [11][12][13] . Only scattered data are available on the molecular features underlying CLPD-NK, mainly provided by approaches targeted to exons of specific genes, with limited discovery power.…”

Mutations found in cell‐free DNAs of patients with malignant lymphoma at remission can derive from clonal hematopoiesis

“…TP53 mutation was reportedly observed in only one of 14 ANKL patients in an exome-wide sequencing study. 28 Although detection of TP53-CHIP has been reported as a risk factor for developing t-MN, [11][12][13] some TP53-carrying CHIP clones themselves are not founding leukemic clones. 11 The significance of monitoring a single specific TP53-CHIP-carrying clone and its predictive value for t-MN remains uncertain.…”

Myeloproliferative and lymphoproliferative disorders: State of the art

“…Based on these recent observations, JAK/STAT signaling has been suggested as a potential therapeutic target in LPN; ruxolitinib has been evaluated as a single agent in a pilot, proof‐of‐concept study in relapsed/refractory (R/R) HL and PMBL; a preliminary report suggested that HL patients may derive greater benefit from this approach…”

“…30 Notably, activating STAT mutations could not initiate leukemic cell proliferation on their own but enhanced signaling through the cytokinecytokine receptor-JAK/STAT axis when provided with a signal from upstream 37 ; in line with this finding, mutations in this signaling pathway have been reported to co-occur, at least in some cases, suggesting that they may interact and cooperate in the oncogenic process. 36 Based on these recent observations, JAK/STAT signaling has been suggested as a potential therapeutic target in LPN [38][39][40] ; ruxolitinib has been evaluated as a single agent in a pilot, proof-of-concept study in relapsed/refractory (R/R) HL and PMBL; a preliminary report suggested that HL patients may derive greater benefit from this approach. 41 This led to a phase II study in advanced, mostly refractory, HL patients: 42 In a population that was quite difficult to address (five median prior lines of treatment), ruxolitinib showed signs of clinical activity, though they were short-lived, with a favorable safety profile, suggesting it might be combined with other therapeutic approaches.…”