Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling.
Although myeloid leukemias are primarily caused by leukemic stem cells, the molecular basis of their transformation remains largely unknown. Here, by analyzing mice with a mutation in the RING finger domain of c-Cbl, we show that the E3 ubiquitin ligase activity of c-Cbl is required to restrict myeloid leukemia development. These mice develop a myeloproliferative disease which progresses to leukemia and involves hematopoietic progenitors that exhibit augmented FLT3 signaling. Suppressing this signaling through matings with FLT3 ligand knockout mice prevents leukemia development. We also observe enhanced c-Kit, Akt and Erk activity, and deregulated expression of leukemia-associated transcription factors in hematopoietic progenitors. The characterization of these perturbations provides direction for therapeutics that may aid the treatment of patients with c-Cbl mutations.
Rathinam
Chozhavendan
C
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Thien
Christine B F
CB
Flavell
Richard A
RA
Langdon
Wallace Y
WY
D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000737:chemistry / Q000378:metabolism*; D054829:RING Finger Domains; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
D008024:Ligands; D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D051057:Proto-Oncogene Proteins c-akt