FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia.
Despite their known transforming properties, the effects of leukemogenic FLT3-ITD mutations on hematopoietic stem and multipotent progenitor cells and on hematopoietic differentiation are not well understood. We report a mouse model harboring an ITD in the murine Flt3 locus that develops myeloproliferative disease resembling CMML and further identified FLT3-ITD mutations in a subset of human CMML. These findings correlated with an increase in number, cell cycling, and survival of multipotent stem and progenitor cells in an ITD dose-dependent manner in animals that exhibited alterations within their myeloid progenitor compartments and a block in normal B cell development. This model provides insights into the consequences of constitutive signaling by an oncogenic tyrosine kinase on hematopoietic progenitor quiescence, function, and cell fate.
Lee
Benjamin H
BH
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. bhlee@partners.org
Tothova
Zuzana
Z
Levine
Ross L
RL
Anderson
Kristina
K
Buza-Vidas
Natalija
N
Cullen
Dana E
DE
McDowell
Elizabeth P
EP
Adelsperger
Jennifer
J
Fröhling
Stefan
S
Huntly
Brian J P
BJ
Beran
Miloslav
M
Jacobsen
Sten Eirik
SE
Gilliland
D Gary
DG
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D007942:Leukemia, Experimental / Q000378:metabolism / Q000473:pathology; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3