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

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 (CBL mut ) 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 CBL mut myeloid malignancies.

journal_name

Genes Dev

journal_title

Genes & development

authors

Lv K,Jiang J,Donaghy R,Riling CR,Cheng Y,Chandra V,Rozenova K,An W,Mohapatra BC,Goetz BT,Pillai V,Han X,Todd EA,Jeschke GR,Langdon WY,Kumar S,Hexner EO,Band H,Tong W

doi

10.1101/gad.297135.117

subject

Has Abstract

pub_date

2017-05-15 00:00:00

pages

1007-1023

issue

10

eissn

0890-9369

issn

1549-5477

pii

gad.297135.117

journal_volume

31

pub_type

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