JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias

• Published in: Genes & development Vol. 32; no. 11-12; pp. 849 - 864
• Main Authors: Kim, Sang-Kyu, Knight, Deborah A, Jones, Lisa R, Vervoort, Stephin, Ng, Ashley P, Seymour, John F, Bradner, James E, Waibel, Michaela, Kats, Lev, Johnstone, Ricky W
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-06-2018
• Subjects: Animals; Antineoplastic Agents - pharmacology; Azepines - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Gene Knockdown Techniques; Humans; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Male; Mice; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - physiopathology; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Receptors, Cytokine - genetics; Research Paper; RNA Interference; Transcriptome; Triazoles - pharmacology; BET bromodomain inhibitor; oncogene addiction; c-Myc; JQ1; ruxolitinib; JAK2; B-cell acute lymphoblastic leukemia
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.307504.117

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
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.