FLT3 receptor in normal and malignant hematopoiesis

Abstract: All hematopoietic cells originate from hematopoietic stem cells (HSCs) residing in the bone marrow (BM). The classical model of hematopoietic lineage commitment, that has been the prevailing model for hematopoiesis, proposes that the first lineage commitment step of HSCs and progenitors results in a strict separation of myelopoiesis and lymphopoiesis. However, an alternative model has already been suggested by introducing the lymphoid-primed multipotent progenitors (LMPPs) which highly express the receptor tyrosine kinase FLT3, and have sustained lymphoid and myeloid potentials, but little or no megakaryocyte/erythroid (MkE) potential. In this work, we further characterized LMPPs by applying clonal single cell culture assay, global gene expression analysis and multiplex single cell PCR assay. We demonstrated that LMPPs could generate myeloid, B- and T- cells at very high frequencies in culture but had very low MkE potential, and that MkE transcriptional priming was downregulated in LMPPs whereas lymphoid priming was upregulated, and lymphoid genes were coexpressed with myeloid genes. We could also show that the MkE potential of LMPP segregated almost entirely with the expression of thrombopoietin receptor (THPOR) in this population. Besides, using RAG1-GFP reporter mice, we could demonstrate that the GM potential is sustained but gradually reduced with increasing levels of lymphoid transcriptional priming within the LMPP compartment, suggesting the lineage restriction process from HSCs to LMPPs occurs as a gradual process. FLT3 plays an important role in normal hematopoiesis. Moreover, gain of function mutations of FLT3 has been reported in about one third of acute myeloid leukemia (AML) patients. The most common mutation of FLT3 is the internal tandem duplication (ITD) of its juxtamembrane domain, which confers a poor clinical prognosis. The clinical outcome is even worse in those patients who lose the FLT3 wild type (WT) gene. Using an Flt3-ITD knockin mouse model crossed with FLT3 receptor knockout mice, we could demonstrate that the development of a myeloproliferative disease in these mice is dependent both on ITD gene dosage as well as the absence of the WT allele. Further, we found that the development of the myeloproliferative disease in Flt3-ITD homozygous mice was FLT3 ligand independent.