The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis

Abstract

The cytokine Fms-like tyrosine kinase 3 ligand (FL) is an important regulator of hematopoiesis. Its receptor, Flt3, is expressed on myeloid, lymphoid and dendritic cell progenitors and is considered an important growth and differentiation factor for several hematopoietic lineages. Activating mutations of Flt3 are frequently found in acute myeloid leukemia (AML) patients and associated with a poor clinical prognosis. In the present review we provide an overview of our current knowledge on the role of FL in the generation of blood cell lineages. We examine recent studies on Flt3 expression by hematopoietic stem cells and its potential instructive action at early stages of hematopoiesis. In addition, we review current findings on the role of mutated FLT3 in leukemia and the development of FLT3 inhibitors for therapeutic use to treat AML. The importance of mouse models in elucidating the role of Flt3-ligand in normal and malignant hematopoiesis is discussed.

Gilteritinib induces PUMA‐dependent apoptotic cell death via AKT/GSK‐3β/NF‐κB pathway in colorectal cancer cells

“…[12][13][14] In patients with acute myeloid leukaemia (AML), FLT3 is frequently mutated and is thus associated with poor prognosis and reduced survival of patients. 9,18 A newly discovered dual FLT3 inhibitor, gilteritinib (ASP2215), 19 remarkably decreases the ability of FLT3positive leukaemia cells to colonize. 17 When FLT3-ITD is expressed in cell line that is factor-dependent, they result in factor-independent growth and malignant transformation.…”

“…17 When FLT3-ITD is expressed in cell line that is factor-dependent, they result in factor-independent growth and malignant transformation. 9,18 A newly discovered dual FLT3 inhibitor, gilteritinib (ASP2215), 19 remarkably decreases the ability of FLT3positive leukaemia cells to colonize. 20 Gilteritinib reduces the extent of FLT3 phosphorylation and its downstream targets in animal models as well as in cell cultures 21 without any obvious toxicity.…”

Direct role of FLT3 in regulation of early lymphoid progenitors

“…Lymphoid‐primed multipotent progenitors (LMPPs) express the highest levels of FLT3 (Adolfsson et al , ), and FLT3 plays a key role in LMPP and CLP maintenance (Sitnicka et al , , ). As recently highlighted (Tsapogas et al , ), because no Flt3 conditional knockout mouse has been generated, it remains unclear to what degree the reductions observed in B lymphocyte and thymocyte progenitors in mice with germ line deletion of FLT3 or FLT3L (Mackarehtschian et al , ; Sitnicka et al , , ), are secondary to loss of LMPPs and/or CLPs prior to becoming programmed for lymphoid‐restricted development, or also reflect a distinct role of FLT3 also in already lymphoid‐restricted progenitors. In fact, the expression of FLT3 in the B‐ and T‐lymphocyte lineages, is restricted to the earliest pre‐proB and early thymic progenitors (ETPs), respectively (Wasserman et al , ; Mansson et al , ; Luc et al , ), progenitors suggested largely to represent not fully lymphoid‐restricted progenitors (Rumfelt et al , ; Luc et al , ).…”

“…Its ligand, FLT3 ligand (FLT3L) exists in a soluble as well as membrane-bound form (Lyman et al, 1995;Lyman & Jacobsen, 1998). Studies in mice have established that FLT3 and FLT3L play an important role in lymphopoiesis (Lyman & Jacobsen, 1998;McKenna et al, 2000;Sitnicka et al, 2002;Tsapogas et al, 2017). Although not expressed on haematopoietic stem cells (HSCs), FLT3 expression is initiated on multipotent progenitors (MPPs) and sustained on common lymphoid progenitors (CLPs), but is only expressed on the very earliest B-cell and T-cell progenitors (Wasserman et al, 1995;Adolfsson et al, 2001Adolfsson et al, , 2005Sitnicka et al, 2002;Boyer et al, 2011;Buza-Vidas et al, 2011;Luc et al, 2012).…”

“…In fact, the expression of FLT3 in the B-and T-lymphocyte lineages, is restricted to the earliest pre-proB and early thymic progenitors (ETPs), respectively (Wasserman et al, 1995;Mansson et al, 2010;Luc et al, 2012), progenitors suggested largely to represent not fully lymphoid-restricted progenitors (Rumfelt et al, 2006;Luc et al, 2012). Establishing to what degree FLT3 plays a direct role in regulating already lymphoid-programmed progenitors, is of particular relevance for the high prevalence of two types of FLT3 driver mutations, internal tandem duplication (ITD) and recurrent FLT3 pointmutations, both associated with a poor clinical outcome in acute leukaemia (Stirewalt & Radich, 2003;Tsapogas et al, 2017), including distinct ETP and B-cell progenitor leukaemia (Armstrong et al, 2004;Neumann et al, 2013).…”