Requirement for p85alpha regulatory subunit of class IA PI3K in myeloproliferative disease driven by an activation loop mutant of KIT.
OBJECTIVE
Oncogenic activation loop mutations of KIT are observed in acute myeloid leukemia (AML) and in myeloproliferative disorders (MPD); however, the signaling pathways that contribute to transformation via these mutations in vivo are not known. Previous studies have demonstrated hyperactivation of p85alpha regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT (KITD816V [human] and KITD814V [murine]). Although p85alpha is hyperphosphorylated and constitutively bound to KITD814V in cell-line models; the physiologic significance of this biochemical phenomenon in KITD814V-induced transformation is not known.


METHODS
Here, we describe the generation of a new mouse model to study KITD814V-induced transformation in myeloid cells as opposed to previously described models that primarily result in the generation of disease resembling acute lymphocytic leukemia.


RESULTS
Our results show that transplantation of KITD814V expressing bone marrow cells from C57/BL6 strain of mice into syngeneic recipients results in a fatal MPD. Importantly, in this model, transplantation of KITD814V expressing p85alpha-deficient bone marrow cells rescues the MPD phenotype.


CONCLUSIONS
Our results describe the generation of a new murine transplant model to study KITD814V-induced transformation and identify p85alpha as potential therapeutic target for the treatment of KITD814V-bearing diseases.
Munugalavadla
Veerendra
V
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Sims
Emily C
EC
Chan
Rebecca J
RJ
Lenz
Stephen D
SD
Kapur
Reuben
R
D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000473:pathology
D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit