JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias
- Author(s)
- Kim, SK; Knight, DA; Jones, LR; Vervoort, S; Ng, AP; Seymour, JF; Bradner, JE; Waibel, M; Kats, L; Johnstone, RW;
- Details
- Publication Year 2018-06-01,Volume 32,Issue #11-12,Page 849-864
- Journal Title
- Genes & Development
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- CSH Press
- Research Division(s)
- Cancer And Haematology
- PubMed ID
- 29907650
- Publisher's Version
- https://doi.org/10.1101/gad.307504.117
- Open Access at Publisher's Site
https://doi.org/10.1101/gad.307504.117- NHMRC Grants
- NHMRC/1122783, NHMRC/1060179, NHMRC/1113577,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-06-27 09:13:25
Last Modified: 2018-08-17 08:49:47