JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias.
Genes Dev
; 32(11-12): 849-864, 2018 06 01.
Article
in En
| MEDLINE
| ID: mdl-29907650
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Janus Kinase 2
/
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Genes Dev
Journal subject:
BIOLOGIA MOLECULAR
Year:
2018
Document type:
Article
Affiliation country: