IntroductionActivating mutations of growth factor receptors (GFRs) are frequent events in many tumor types. A common theme of such mutations is the acquisition of mutant allele specific imbalance (MASI) either because of copy number-neutral loss of heterozygosity or mutant allele amplification, particularly during disease progression. 1 For example, MASI affects epidermal GFR (EGFR) mutations in lung cancer and glioblastoma, 2 KIT mutations in gastrointestinal tumors, 3 and MPL mutations in myelofibrosis. 4 MASI of activated GFRs may accelerate disease through a simple gene-dosage effect, although it is also possible that loss of the wild-type (WT) protein enhances the impact of the mutant allele, for example, by enhancing formation of mutant homodimers. Although the impact of mutant GFR gene dosage has been modeled in vivo, [5][6][7][8] less is known about the impact of loss of the second WT allele. In the case of activating RET mutations in endocrine neoplasia, deletion of the WT allele occurs in connection with tumor progression, 9,10 although in a mouse model (Ret MEN2B ), hemizygous Ret mutations were not biologically distinct from heterozygous mutations. 11 Although many mutations confer a degree of ligand-independent GFR activation, in vitro studies often observe an additional impact of exogenous ligand. EGFR, 12 platelet-derived GFR, 13 and MET receptor tyrosine kinase mutations 14 are all dependent on their ligands for full transforming activity.FMS-like tyrosine kinase3 (FLT3) is a receptor tyrosine kinase expressed on normal hematopoietic multipotent progenitors 15 and acute leukemia blast cells. 16 Internal tandem duplications (ITDs) within the juxtamembrane domain of FLT3, inducing ligandindependent dimerization and constitutive signaling, occur in ϳ 25% of acute myeloid leukemia (AML). 16 FLT3-ITD is associated with high relapse rate and poor overall survival in AML. 16,17 As with other GFR mutations, MASI at the FLT3 locus in FLT3-ITD ϩ AML is associated with a particularly poor prognosis 18 and occurs because of copy number-neutral loss of heterozygosity with consequent ITD homozygosity. 19 Although MASI is uncommon at diagnosis (ϳ 15% of ITD ϩ cases), it is frequently observed at relapse. 20 Mice heterozygous for an ITD at the endogenous Flt3 locus develop chronic myeloproliferative disease (MPD) with expanded myeloid progenitor cells. 7,21 Importantly, ITD homozygosity results in a more severe MPD phenotype. 7 However, it remains unclear to what degree disease progression only reflects an ITD gene dosage effect and/or whether loss of the WT allele itself might accelerate the phenotype of heterozygous ITDs.Although ITDs clearly induce FLT3 ligand (FL)-independent autophosphorylation of FLT3, 16 addition of exogenous FL to FL-deficient ITD cell lines results in enhanced FLT3 receptor activation. 22 Furthermore, FL increases ITD-induced activation of STAT pathways in vitro, a mechanism proposed to mediate resistance to FLT3 inhibitors. 23 It has recently been suggested that increases in FL levels ...