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

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


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.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cytokines / metabolism
  • Enzyme Stability
  • Hematopoietic Stem Cells / enzymology
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism*
  • Leukemia, Myeloid, Acute / enzymology*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / physiopathology*
  • Membrane Proteins
  • Mice
  • Mutation
  • Proteolysis
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Signal Transduction / genetics
  • Ubiquitination


  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Lnk protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins c-cbl
  • Janus Kinase 2