title: Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development.
abstract: Mice deficient in c-fms-like tyrosine kinase 3 (FLT3) signaling have reductions in early multipotent and lymphoid progenitors, whereas no evident myeloid phenotype has been reported. However, activating mutations of Flt3 are among the most common genetic events in acute myeloid leukemia and mice harboring internal tandem duplications within Flt3 (Flt3-ITD) develop myeloproliferative disease, with characteristic expansion of granulocyte-monocyte (GM) progenitors (GMP), possibly compatible with FLT3-ITD promoting a myeloid fate of multipotent progenitors. Alternatively, FLT3 might be expressed at the earliest stages of GM development. Herein, we investigated the expression, function, and role of FLT3 in recently identified early GMPs. Flt3-cre fate-mapping established that most progenitors and mature progeny of the GM lineage are derived from Flt3-expressing progenitors. A higher expression of FLT3 was found in preGMP compared with GMP, and preGMPs were more responsive to stimulation with FLT3 ligand (FL). Whereas preGMPs and GMPs were reduced in Fl(-/-) mice, megakaryocyte-erythroid progenitors were unaffected and lacked FLT3 expression. Notably, mice deficient in both thrombopoietin (THPO) and FL had a more pronounced GMP phenotype than Thpo(-/-) mice, establishing a role of FL in THPO-dependent and -independent regulation of GMPs, of likely significance for myeloid malignancies with Flt3-ITD mutations.
authors.affiliation: Hematopoietic Stem Cell Laboratory, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Böiers
authors.forename: Natalija
authors.initials: N
authors.lastname: Buza-Vidas
authors.forename: Christina T
authors.initials: CT
authors.lastname: Jensen
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: Pronk
authors.forename: Shabnam
authors.initials: S
authors.lastname: Kharazi
authors.forename: Lilian
authors.initials: L
authors.lastname: Wittmann
authors.forename: Ewa
authors.initials: E
authors.lastname: Sitnicka
authors.forename: Anne
authors.initials: A
authors.lastname: Hultquist
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D022423:Myeloid Cells / Q000166:cytology; D015398:Signal Transduction / Q000502:physiology; D013926:Thrombopoietin / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C084881:flt3 ligand protein; D013926:Thrombopoietin; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3