B?hmer FD, Karagyozov L, Uecker A, et al. medical trials and have been associated with transient medical responses. In recent years, efforts have been made to develop more specific and potent inhibitors of FLT3 for medical investigation. One such agent, AC220, has shown great promise and dramatic reactions in Seocalcitol early-phase tests of individuals with AML [9]. FLT3 like a Target was first cloned individually by two organizations in the early Seocalcitol 1990s [10, 11]. It resides on chromosome 13 and is comprised of 24 exons [12C14]. FLT3 is considered a type III receptor tyrosine kinase, a class that also includes KIT and platelet-derived growth element receptor (PDGFR), proteins with very close homology to FLT3 [3, 15, 16]. FLT3 consists of an extracellular region with five immunoglobulin-like domains, a transmembrane region, a short intracellular juxtamembrane portion, followed by an intracellular tyrosine kinase website (TKD). Upon binding of its ligand, FLT3 dimerizes, leading to eventual autophosphorylation within the Seocalcitol inner leaflet of the membrane, with subsequent activation of the tyrosine kinase. phosphoinositide 3-kinase (PI3K), AKT, mitogen-activated protein kinase (MAPK), and transmission transducer and activator of transcription (STAT)-5 are all significant mediators of downstream FLT3 signaling (Fig. 1) [17C25]. Open in FLJ11071 a separate window Physique 1. Simplified diagram of signaling cascades downstream of FLT3 that are thought to promote leukemogenesis. Abbreviations: BAD, Bcl-2-associated death promoter; ERK, extracellular signalCrelated kinase; FL, FLT3 Seocalcitol ligand; FLT3, FMS-like tyrosine kinase 3; Grb2, growth factor receptor-bound protein 2; MEK, mitogen-activated protein kinase/ERK kinase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; PIM1, proto-oncogene serine/threonine-protein kinase 1; PIP2, phosphatidylinositol-bisphosphate; PIP3, phosphatidylinositol-trisphosphate; Rheb, Ras homolog enriched in brain; SOS, child of sevenless; STAT-5, transmission transducer and activator of transcription 5; TSC, tuberous sclerosis protein. Figure derived from one obtained courtesy of Dr. Mark Levis, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD. The cytokine that binds FLT3, the FLT3 ligand (FL), is usually ubiquitous to most tissues but appears functionally important only in hematopoietic and neural tissue [26, 27]. In the hematopoietic environment, FLT3 expression exists predominantly in CD34+ cells, although CD34? precursors of dendritic cells also express FLT3. FLT3 is a key mediator of early hematopoiesis and is involved with the reconstitution of early multilineage myeloid precursors [11, 28C30]. Disruption of FLT3 signaling in murine models is not lethal but does lead to a significant reduction in hematopoietic precursors. Specifically, when the gene was disrupted in mice, the numbers of myeloid and B lymphoid cells were markedly lower in the bone marrow. Interestingly, the numbers of dendritic and natural killer cells were also significantly lower in the spleen and thymus [31]. Overexpression of FLT3, or its constitutive activation, appears to play a major role in leukemias. Both FL and the FLT3 receptor have been demonstrated in the majority of human leukemia cell lines [32, 33]. FLT3 is usually expressed in higher amounts in AML blasts than in cells from normal bone marrow. Additionally, in this setting, its expression is usually no longer tightly associated with CD34 expression as it is in normal precursors. Indeed, the large majority of evaluated AML cell lines have amplified activity of FLT3 [34C36]. Some of these cells exhibited overexpression of WT mutation discovered in AML, and are found in approximately 23% of patients with AML. Seocalcitol These mutations localize to the juxtamembrane domain name of the receptor tyrosine kinase, where they presumably offset the unfavorable regulatory functions of this domain name [41C44]. Another category of mutations consists of activating point mutations within the activation loop of the kinase domain name, mostly localized at the aspartate 835 (D835) residue and found in an additional 7% of patients [12, 45]. mutations result in constitutive activation, leading in turn to activation of STAT-5 as well as the MAPK and AKT signaling cascades. This results in suppression of apoptosis and dysregulated cell proliferation [38, 46, 47]. The ITD mutations, in particular, have been consistently found to have a unfavorable prognostic impact. This was confirmed, in large part, by studies of banked AML samples from the European cooperative groups.