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Genes Dev. 2017 May 15;31(10):1007-1023. doi: 10.1101/gad.297135.117. Epub 2017 Jun 13.

CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies.

Author information

1
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
2
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
Progenra, Inc., Malvern, Pennsylvania 19355, USA.
4
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 6819, USA.
5
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 6819, USA.
6
Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
7
Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
8
School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia.

Abstract

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.

KEYWORDS:

Janus kinase 2 (JAK2); acute myeloid leukemia (AML); chronic myelomonocytic leukemia (CMML); hematopoietic stem cells (HSCs); juvenile myelomonocytic leukemia (JMML); signaling; ubiquitin

PMID:
28611190
PMCID:
PMC5495118
DOI:
10.1101/gad.297135.117
[Indexed for MEDLINE]
Free PMC Article

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