Unknown

Dataset Information

0

Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model.


ABSTRACT: Constitutive activation of FMS-like tyrosine kinase 3 (FLT3) by internal tandem duplication (ITD) mutations is one of the most common molecular alterations known in acute myeloid leukemia (AML). To investigate the role FLT3/ITD mutations play in the development of leukemia, we generated a FLT3/ITD knock-in mouse model by inserting an ITD mutation into the juxtamembrane domain of murine Flt3. FLT3wt/ITD mice developed myeloproliferative disease, characterized by splenomegaly, leukocytosis, and myeloid hypercellularity, which progressed to mortality by 6 to 20 months. Bone marrow (BM) and spleen from FLT3wt/ITD mice had an increased fraction of granulocytes/monocytes and dendritic cells, and a decreased fraction of B-lymphocytes. No sign of acute leukemia was observed over the lifetime of these mice. BM from FLT3wt/ITD mice showed enhanced potential to generate myeloid colonies in vitro. BM from FLT3wt/ITD mice also produced more spleen colonies in the in vivo colony-forming unit (CFU)-spleen assay. In the long-term competitive repopulation assay, BM cells from FLT3wt/ITD mice outgrew the wild-type competitor cells and showed increased myeloid and reduced lymphoid expansion activity. In summary, our data indicate that expression of FLT3/ITD mutations alone is capable of conferring normal hematopoietic stem/progenitor cells (HSPCs) with enhanced myeloid expansion. It also appears to suppress B lymphoid maturation. Additional cooperative events appear to be required to progress to acute leukemia.

SUBMITTER: Li L 

PROVIDER: S-EPMC2275036 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model.

Li Li L   Piloto Obdulio O   Nguyen Ho Bao HB   Greenberg Kathleen K   Takamiya Kogo K   Racke Frederick F   Huso David D   Small Donald D  

Blood 20080201 7


Constitutive activation of FMS-like tyrosine kinase 3 (FLT3) by internal tandem duplication (ITD) mutations is one of the most common molecular alterations known in acute myeloid leukemia (AML). To investigate the role FLT3/ITD mutations play in the development of leukemia, we generated a FLT3/ITD knock-in mouse model by inserting an ITD mutation into the juxtamembrane domain of murine Flt3. FLT3wt/ITD mice developed myeloproliferative disease, characterized by splenomegaly, leukocytosis, and my  ...[more]

Similar Datasets

| S-EPMC3876267 | biostudies-literature
| S-EPMC10079527 | biostudies-literature
| S-EPMC8410575 | biostudies-literature
| S-EPMC1895777 | biostudies-literature
| S-EPMC8113057 | biostudies-literature
| S-EPMC3764066 | biostudies-literature
| S-EPMC9197875 | biostudies-literature
| S-EPMC4936702 | biostudies-literature
| S-EPMC7484840 | biostudies-literature
| S-EPMC6561101 | biostudies-literature