Abstract：
:Internal tandem duplication (ITD) mutations within the FMS-like tyrosine kinase-3 (FLT3) render the receptor constitutively active driving proliferation and survival in leukemic blasts. Expression of FLT3-ITD from the endogenous promoter in a murine knockin model results in progenitor expansion and a myeloproliferative neoplasm. In this study, we show that this expansion begins with overproliferation within a compartment of normally quiescent long-term hematopoietic stem cells (LT-HSCs), which become rapidly depleted. This depletion is reversible upon treatment with the small molecule inhibitor Sorafenib, which also ablates the disease. Although the normal LT-HSC has been defined as FLT3(-) by flow cytometric detection, we demonstrate that FLT3 is capable of playing a role within this compartment by examining the effects of constitutively activated FLT3-ITD. This indicates an important link between stem cell quiescence/homeostasis and myeloproliferative disease while also giving novel insight into the emergence of FLT3-ITD mutations in the evolution of leukemic transformation.
journal_name
Cell Stem Celljournal_title
Cell stem cellauthors
Chu SH,Heiser D,Li L,Kaplan I,Collector M,Huso D,Sharkis SJ,Civin C,Small Ddoi
10.1016/j.stem.2012.05.027subject
Has Abstractpub_date
2012-09-07 00:00:00pages
346-58issue
3eissn
1934-5909issn
1875-9777pii
S1934-5909(12)00367-0journal_volume
11pub_type
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