Journal
GENES & DEVELOPMENT
Volume 32, Issue 11-12, Pages 849-864Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.307504.117
Keywords
JAK2; B-cell acute lymphoblastic leukemia; ruxolitinib; oncogene addiction; c-Myc; JQ1; BET bromodomain inhibitor
Categories
Funding
- Cancer Council Victoria
- Cancer Therapeutics Cooperative Research Centre PhD Top-Up Scholarship
- Melbourne International Research Scholarship
- National Health and Medical Research Council (NHMRC)
- NHMRC project [APP1122783, APP 1060179]
- NHMRC Program [454569, 1113577]
- NHMRC Senior Principal Research Fellowship
- Kids' Cancer Project
Ask authors/readers for more resources
Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2(Y1007/1008) hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available