期刊
LEUKEMIA
卷 31, 期 4, 页码 934-944出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.280
关键词
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资金
- Leukemia and Lymphoma Research
- Cancer Research UK
- NIHR Cambridge Biomedical Research Centre
- Cambridge Experimental Cancer Medicine Centre
- Leukemia & Lymphoma Society of America
- Austrian Science Foundation [J 3578-B21]
- Kay Kendall Leukaemia Fund clinical research fellowship
- Cancer Research UK Clinician Scientist Fellowship
- European Research Council
- MRC (UK)
- Bloodwise
- Cambridge NIHR
- WT/MRC Stem Cell centre grant
- Wellcome Trust to the Cambridge Institute for Medical Research [100140/z/12/z]
- Wellcome Trust-MRC Cambridge Stem Cell Institute [097922/Z/11/Z]
- Medical Research Council [MC_PC_12009, MR/M010392/1, 1479733] Funding Source: researchfish
- Worldwide Cancer Research [14-1069] Funding Source: researchfish
- MRC [MR/M010392/1] Funding Source: UKRI
Most myeloproliferative neoplasm (MPN) patients lacking JAK2 mutations harbour somatic CALR mutations that are thought to activate cytokine signalling although the mechanism is unclear. To identify kinases important for survival of CALR-mutant cells, we developed a novel strategy (KISMET) that utilizes the full range of kinase selectivity data available from each inhibitor and thus takes advantage of off-target noise that limits conventional small-interfering RNA or inhibitor screens. KISMET successfully identified known essential kinases in haematopoietic and non-haematopoietic cell lines and identified the mitogen activated protein kinase (MAPK) pathway as required for growth of the CALR-mutated MARIMO cells. Expression of mutant CALR in murine or human haematopoietic cell lines was accompanied by myeloproliferative leukemia protein (MPL)-dependent activation of MAPK signalling, and MPN patients with CALR mutations showed increased MAPK activity in CD34 cells, platelets and megakaryocytes. Although CALR mutations resulted in protein instability and proteosomal degradation, mutant CALR was able to enhance megakaryopoiesis and pro-platelet production from human CD34(+) progenitors. These data link aberrant MAPK activation to the MPN phenotype and identify it as a potential therapeutic target in CALR-mutant positive MPNs.
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