FLT3-ITD Knockin Impairs Hematopoietic Stem Cell Quiescence/Homeostasis, Leading to Myeloproliferative Neoplasm

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. º FLT3-ITD perturbs normal mouse hematopoietic stem cell homeostasis º FLT3 is expressed and capable of exerting functional effects in murine LT-HSCs º FLT3-ITD leads to depletion of murine LT-HSCs through loss of quiescence º MPN and HSC defects are simultaneously reversed by Sorafenib treatment The FLT3 receptor, frequently mutated in acute myeloid leukemia, is not believed to be expressed in HSCs. A constitutively active FLT3-ITD mutation in mice drives depletion of LT-HSCs and is coupled with rapid myeloproliferation, suggesting an unrecognized link between HSCs homeostasis and disease.