期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-03987-2
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资金
- European Research Council (M-IMM project)
- Academy of Finland [292605, 287224]
- Tekes - the Finnish Funding Agency for Innovation [6113/31/2016]
- Sigrid Juselius Foundation
- Instrumentarium Science foundation
- Cancer Society of Finland
- Finnish Cancer Institute
- City of Hope Cancer Center Support Grant [P30CA33572]
- Lymphoma SPORE developmental project grant [1 P50 CA 136411-01 01A1 PP-4]
- Ministry of Education, Culture, Sports, Science and Technology of Japan [KAKEN 15K09471]
- Japan Leukemia Research Fund
- Takeda Pharmaceutical (inst)
- Cyugai Pharmaceutical (inst)
- Kyowa Hakko-Kirin (inst)
- Pfizer (inst)
- Finnish special governmental subsidy for health sciences, research and training
- Grants-in-Aid for Scientific Research [15K09471] Funding Source: KAKEN
- Academy of Finland (AKA) [292605, 287224, 292605, 287224] Funding Source: Academy of Finland (AKA)
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.
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