Journal
BLOOD
Volume 101, Issue 5, Pages 1984-1986Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2002-08-2635
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Funding
- NCI NIH HHS [1 K08 CA096579-01, R01 CA762714, R01 CA 74177-06] Funding Source: Medline
- NICHD NIH HHS [K12-HD00850] Funding Source: Medline
- NIDDK NIH HHS [P30 DK49218] Funding Source: Medline
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The development of molecularly targeted treatments of adult leukemias warrants investigation of these targets in similar pediatric leukemias. The NF1 tumor suppressor gene, which encodes a GTPase activating protein for p21(ras), is frequently inactivated in juvenile myelomonocytic leukemia (JMML). Other patients with JMML acquire activating RAS gene mutations. Recipient mice reconstituted with Nf1(-/-) fetal hematopoietic cells develop a myeloproliferative disease (MPD) that models the human disease. JMML arises from clonal expansion of a hematopoietic stem cell, and JMML cells and murine Nf1(-/-) hematopoietic cells are hypersensitive to granulocyte macrophage-colony stimulating factor and KitL, the ligand for c-kit. We generated embryos doubly mutant for the W-v allele of c-kit and Nf1 to ask if reduction of c-kit activity would delay or prevent the development of MPD. Despite a reduction in c-kit activity to approximately 10% of wild-type levels, Nf1(-/-); W-v/W-v cells induced MPD in recipient mice.
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