Journal
GENES & DEVELOPMENT
Volume 31, Issue 10, Pages 1007-1023Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.297135.117
Keywords
hematopoietic stem cells (HSCs); Janus kinase 2 (JAK2); ubiquitin; signaling; chronic myelomonocytic leukemia (CMML); juvenile myelomonocytic leukemia (JMML); acute myeloid leukemia (AML)
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Funding
- National Institutes of Health [R01HL095675, CA87986, CA105489]
- National Health and Medical Research [1057762, 1101318]
- Gabrielle's Angel Foundation for Cancer Research
- Alex's Lemonade for Childhood Cancer Research
- Dr. Rafael Bonita Memorial Fund for Cancer Research
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Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of CBL/CBL-B or LNK abrogated JAK2 ubiquitination, extended JAK2 half-life, and enhanced JAK2 signaling and cell growth in human cell lines as well as primary murine HSPCs. Built on these findings, we showed that JAK inhibitor (JAKi) significantly reduced aberrant HSPCs and mitigated leukemia development in a mouse model of aggressive myeloid leukemia driven by loss of Cbl and Cbl-b. Importantly, primary human CBL mutated (CBLmut) leukemias exhibited increased JAK2 protein levels and signaling and were hypersensitive to JAKi. Loss-of-function mutations in CBL E3 ubiquitin ligases are found in a wide range of myeloid malignancies, which are diseases without effective treatment options. Hence, our studies reveal a novel signaling axis that regulates JAK2 in normal and malignant HSPCs and suggest new therapeutic strategies for treating CBLmut myeloid malignancies.
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