JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias
- Sang-Kyu Kim1,2,
- Deborah A. Knight1,
- Lisa R. Jones1,2,
- Stephin Vervoort1,2,
- Ashley P. Ng3,4,
- John F. Seymour1,2,
- James E. Bradner5,
- Michaela Waibel1,2,
- Lev Kats1,2 and
- Ricky W. Johnstone1,2
- 1The Peter MacCallum Cancer Centre, Melbourne, 3000 Victoria, Australia;
- 2The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3052 Victoria, Australia;
- 3Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 Victoria, Australia;
- 4Department of Medical Biology, University of Melbourne, Parkville, 3010 Victoria, Australia;
- 5Novartis Institutes for BioMedical (NIBR) Research, Cambridge, Massachusetts 02139, USA
- Corresponding author: ricky.johnstone{at}petermac.org
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 JAK2Y1007/1008 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.
Keywords
- JAK2
- B-cell acute lymphoblastic leukemia
- ruxolitinib
- oncogene addiction
- c-Myc
- JQ1
- BET bromodomain inhibitor
Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.307504.117.
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Freely available online through the Genes & Development Open Access option.
- Received September 22, 2017.
- Accepted May 7, 2018.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.