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Updated: Aug 8, 2026
A Detailed Protocol for Characterizing the Murine C1498 Cell Line and its Associated Leukemia Mouse Model
Published on: October 14, 2016
Leukemic potential of doubly mutant Nf1 and Wv hematopoietic cells
David A Ingram1, Mary Jo Wenning, Kevin Shannon
1Indiana University School of Medicine, Herman B. Wells Center for Pediatric Research, Department of Microbiology/Immunology, Indianapolis, IN 46202, USA. dingram@iupui.edu
Abstract:
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 Wv 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-/-;Wv/Wv cells induced MPD in recipient mice.
Insights
Juvenile myelomonocytic leukemia (JMML) involves the NF1 gene. Reducing c-kit activity in Nf1-deficient cells did not prevent myeloproliferative disease (MPD) development in mice.
Area of Science:
- Oncology
- Genetics
- Hematology
Background:
- The NF1 tumor suppressor gene is frequently inactivated in juvenile myelomonocytic leukemia (JMML).
- Activating RAS gene mutations are also observed in JMML patients.
- Nf1-/- fetal hematopoietic cells induce a myeloproliferative disease (MPD) in mice, modeling human JMML.
Purpose of the Study:
- To investigate the role of c-kit signaling in NF1-associated MPD.
- To determine if reducing c-kit activity can prevent or delay MPD development in a murine model.
Main Methods:
- Generation of double mutant embryos (Nf1-/-; Wv/Wv) with reduced c-kit activity.
- Hematopoietic stem cell transplantation into recipient mice.
- Monitoring for the development of MPD.
Main Results:
- Nf1-/-;Wv/Wv cells exhibited approximately 10% of wild-type c-kit activity.
- Despite reduced c-kit activity, Nf1-/-;Wv/Wv cells induced MPD in recipient mice.
- This suggests that reduced c-kit signaling does not prevent MPD in this model.
Conclusions:
- NF1 deficiency drives MPD independently of significant c-kit signaling.
- Targeting c-kit may not be a sufficient therapeutic strategy for NF1-associated MPD.
- Further research is needed to understand the complex pathways involved in JMML pathogenesis.
