Abstract 2862

Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are overlap myelodysplastic/myeloproliferative neoplasia (MDS/MPN) syndromes that respond poorly to conventional treatment regimens. Both diseases are characterized by aberrant N-Ras, K-Ras, Cbl, and SHP-2 proteins, which are not attractive drug target candidates. Focus has shifted to downstream effector pathways, which include Raf/MEK/ERK, phosphoinositide-3-OH kinase (PI3K)/Akt, and Ral-GDS/Ral-A cascades. However, it is unclear which pathways, if any, should be targeted. In part to address this question, we previously developed a mouse model of CMML and JMML by expressing a conditional “knock-in” KrasG12D oncogene in bone marrow. Our earlier studies showed that inhibition of MEK yields a significant reduction in disease burden in this model, including reduced leukocytosis, improved anemia and enhanced survival. Here, we interrogate the role of the PI3K/Akt pathway in KrasG12D driven MPN and further explore which specific pathways are responsible for leukemogenesis due to hyperactive Ras. We administered GDC-0941, a selective PI3K inhibitor, to Mx1-Cre, KrasG12D mutant mice Mice with well established MPN and wild-type (WT) littermates were randomly chosen to receive daily oral administration of GDC-0941 or a control vehicle. Treated mice exhibited dramatic corrections of leukocytosis and anemia as well as decrease in splenomegaly. Flow cytometry of bone marrow and peripheral populations also imply that GDC-0941 treatment corrects the aberrant proliferation, amends differentiation of bone marrow progenitors, and revives ineffective erythropoiesis found in KrasG12D mice. Treatment also resulted in markedly improved survival of KrasG12D mice; virtually all KrasG12Dmice in the treatment arm outlived their control counterparts. Our data suggest PI3K inhibition may play a role in suppressing hematologic dysfunction in JMML and CMML patients. Potential crosstalk between PI3K and MEK signaling further suggest that combinatorial activities of PI3K and MEK inhibition should be investigated.

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Disclosures:

Friedman:Genentech, Inc.: Employment. Sampath:Genentech, Inc.: Employment.

Topics:
1-phosphatidylinositol 3-kinase, abnormal hematology findings, juvenile myelomonocytic leukemia, k-ras oncogene, leukemia, myelomonocytic, chronic, mice, phosphoinositide 3-kinase, anemia, leukocytosis, administration, oral

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Author notes

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Asterisk with author names denotes non-ASH members.

© 2012 by The American Society of Hematology
2012
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