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Ref Type Journal Article
PMID (11756186)
Authors Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG
Title FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model.
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Abstract Text FLT3 receptor tyrosine kinase is expressed on lymphoid and myeloid progenitors in the hematopoietic system. Activating mutations in FLT3 have been identified in approximately 30% of patients with acute myelogenous leukemia, making it one of the most common mutations observed in this disease. Frequently, the mutation is an in-frame internal tandem duplication (ITD) in the juxtamembrane region that results in constitutive activation of FLT3, and confers interleukin-3 (IL-3)-independent growth to Ba/F3 and 32D cells. FLT3-ITD mutants were cloned from primary human leukemia samples and assayed for transformation of primary hematopoietic cells using a murine bone marrow transplantation assay. FLT3-ITDs induced an oligoclonal myeloproliferative disorder in mice, characterized by splenomegaly and leukocytosis. The myeloproliferative phenotype, which was associated with extramedullary hematopoiesis in the spleen and liver, was confirmed by histopathologic and flow cytometric analysis. The disease latency of 40 to 60 days with FLT3-ITDs contrasted with wild-type FLT3 and enhanced green fluorescent protein (EGFP) controls, which did not develop hematologic disease (> 200 days). These results demonstrate that FLT3-ITD mutant proteins are sufficient to induce a myeloproliferative disorder, but are insufficient to recapitulate the AML phenotype observed in humans. Additional mutations that impair hematopoietic differentiation may be required for the development of FLT3-ITD-associated acute myeloid leukemias. This model system should be useful to assess the contribution of additional cooperating mutations and to evaluate specific FLT3 inhibitors in vivo.

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Molecular Profile Treatment Approach
FLT3 Y599_D600insGLYVDFREYEY FLT3 Inhibitor
FLT3 D835X FLT3 Inhibitor
FLT3 act mut FLT3 Inhibitor
FLT3 over exp FLT3 Inhibitor
FLT3 V579A FLT3 Inhibitor
FLT3 D835H FLT3 Inhibitor
FLT3 Y599_D600insEYEYEYEY FLT3 Inhibitor
FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE FLT3 Inhibitor
FLT3 amp FLT3 Inhibitor
FLT3 Y572del FLT3 Inhibitor
FLT3 D835Y FLT3 Inhibitor
FLT3 D835del FLT3 Inhibitor
FLT3 I836S FLT3 Inhibitor
FLT3 K663Q FLT3 Inhibitor
FLT3 I836T FLT3 Inhibitor
FLT3 I867S FLT3 Inhibitor
FLT3 Y599_D600insSTDNEYFYVDFREYEY FLT3 Inhibitor
FLT3 S840_N841insGS FLT3 Inhibitor
FLT3 Y842H FLT3 Inhibitor
FLT3 E573del FLT3 Inhibitor
FLT3 I836D FLT3 Inhibitor
FLT3 E598_Y599insVAYVDFREYE FLT3 Inhibitor
FLT3 exon 14 ins FLT3 Inhibitor
FLT3 I836L FLT3 Inhibitor
FLT3 G846S FLT3 Inhibitor
FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL FLT3 Inhibitor
FLT3 S584_F605dup FLT3 Inhibitor
FLT3 D839G FLT3 Inhibitor
FLT3 F590_F605dup FLT3 Inhibitor
FLT3 Y599_D600insPAPQIMSTSTLISENMNIA FLT3 Inhibitor
FLT3 D835G FLT3 Inhibitor
FLT3 F594_R595insGTGSSDNEYFYVDF FLT3 Inhibitor
FLT3 S584_D600dup FLT3 Inhibitor
FLT3 L601_K602insNVDFREYEYDL FLT3 Inhibitor
FLT3 E598_Y599del FLT3 Inhibitor
FLT3 D835E FLT3 Inhibitor
FLT3 F612_G613insQGFYVDFREYEYDLKWEFPRENLEF FLT3 Inhibitor
FLT3 D835N FLT3 Inhibitor
FLT3 D593_D600dup FLT3 Inhibitor
FLT3 I836del FLT3 Inhibitor
FLT3 Y597_E598insDEYFYVDFREY FLT3 Inhibitor
FLT3 D586_E596dup FLT3 Inhibitor
FLT3 R834Q FLT3 Inhibitor
FLT3 L576R FLT3 Inhibitor
FLT3 R595_L601dup FLT3 Inhibitor
FLT3 E598_F612dup FLT3 Inhibitor
FLT3 Y599_E604dup FLT3 Inhibitor
FLT3 M578_E598dup FLT3 Inhibitor
FLT3 D835L FLT3 Inhibitor
FLT3 F594Y FLT3 Inhibitor
FLT3 S451F FLT3 Inhibitor
FLT3 D835A FLT3 Inhibitor
FLT3 F590_Y591delinsGD FLT3 Inhibitor
FLT3 F594C FLT3 Inhibitor
FLT3 Y597_E598insAGSSDNEYFYVDFREY FLT3 Inhibitor
FLT3 N676K FLT3 Inhibitor
FLT3 Y572C FLT3 Inhibitor
FLT3 N587_D600dup FLT3 Inhibitor
FLT3 K614_G617del FLT3 Inhibitor
FLT3 V592A FLT3 Inhibitor
FLT3 D835V FLT3 Inhibitor
FLT3 F594_D600dup FLT3 Inhibitor
FLT3 S585_F594dup FLT3 Inhibitor
FLT3 N841I FLT3 Inhibitor
FLT3 Y842C FLT3 Inhibitor
FLT3 E604_F605insSPRGGNEYFYVDFREYEYDLKWE FLT3 Inhibitor
FLT3 V592G FLT3 Inhibitor
FLT3 Y597_K602dup FLT3 Inhibitor
FLT3 D835K FLT3 Inhibitor
FLT3 S941_F942insRVS FLT3 Inhibitor
FLT3 S574del FLT3 Inhibitor
FLT3 E598_Y599insSGSSDNEYFYVDFREYE FLT3 Inhibitor
FLT3 R595_E596insDYVDFR FLT3 Inhibitor
FLT3 F590_D593delinsLY FLT3 Inhibitor
FLT3 A680V FLT3 Inhibitor
FLT3 W603_E604insDREYEYDLKW FLT3 Inhibitor
FLT3 G613_K614insYVDFREYEYDLKWEFRPRENLEFG FLT3 Inhibitor
FLT3 Q575del FLT3 Inhibitor
FLT3 F594L FLT3 Inhibitor
FLT3 E598_Y599insDVDFREYE FLT3 Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FLT3 E598_Y599del deletion gain of function FLT3 E598_Y599del results in the deletion of two amino acids in the juxtamembrane domain of the Flt3 protein from amino acid 598 to 599 (PMID: 11756186). E598_Y599del confers a gain of function to Flt3 as demonstrated by increased Flt3 downstream signaling, decreased apoptosis, clonogenic growth, and cytokine-independent growth in cultured cells (PMID: 26012842).
FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE insertion gain of function FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE results in the insertion of 22 amino acids in the cytoplasmic juxtamembrane domain of the Flt3 protein between amino acids E598 and Y599 (PMID: 11756186). E598_Y599insGLVQVTGSSDNEYFYVDFREYE confers a gain of function on Flt3 protein as indicated by transformation of cells in culture and induction of myeloproliferative disorder in mouse models (PMID: 11756186).
FLT3 F590_D593delinsLY indel gain of function FLT3 F590_D593delinsLY results in a deletion of four amino acids in the juxtamembrane domain of the Flt3 protein from amino acids 590 to 593, combined with the insertion of a leucine (L) and a tyrosine (Y) at the same site (PMID: 11756186). F590_D593delinsLY confers a gain of function to Flt3 as demonstrated by increased Flt3 downstream signaling, decreased apoptosis, weak clonogenic growth, and cytokine-independent growth in cultured cells (PMID: 26012842).
FLT3 F590_F605dup duplication gain of function FLT3 F590_F605dup indicates the insertion of 16 duplicate amino acids, phenylalanine (F)-590 through phenylalanine (F)-605, in the juxtamembrane domain of the Flt3 protein (PMID: 11756186). F590_F605dup results in constitutive phosphorylation of Flt3, activation of Stat5 and Erk signaling, and transformation of cells in culture (PMID: 10698507).
FLT3 F590_Y591delinsGD indel gain of function FLT3 F590_Y591delinsGD results in a deletion of 2 amino acids in the juxtamembrane domain of the Flt3 protein from amino acids 590 to 591, combined with the insertion of a glycine (G) and an aspartic acid (D) at the same site (PMID: 11756186). F590_Y591delinsGD results in constitutive phosphorylation of Flt3, activation of Stat5 signaling, and transformation of cells in culture (PMID: 16410449).
FLT3 G613_K614insYVDFREYEYDLKWEFRPRENLEFG insertion gain of function - predicted FLT3 G613_K614insYVDFREYEYDLKWEFRPRENLEFG (F612_G613insGYVDFREYEYDLKWEFRPRENLEF) results in the insertion of 24 amino acids in the protein kinase domain of the Flt3 protein between amino acids 613 and 614 (UniProt.org). G613_K614insYVDFREYEYDLKWEFRPRENLEFG results in transformation of cultured cells (PMID: 11756186), and therefore, is predicted to lead to a gain of Flt3 protein function.
FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL insertion gain of function FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL results in the insertion of 28 amino acids in the juxtamembrane domain of the Flt3 protein between amino acids L610 and E611 (UniProt.org, PMID: 11756186). L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL results in constitutive phosphorylation of Flt3, activation of Stat5 and Mapk signaling, and transformation of cultured cells (PMID: 10698507, PMID: 11756186).
FLT3 R595_L601dup duplication gain of function FLT3 R595_L601dup (also referred to as FLT3 L601_K602insREYEYDL) indicates the insertion of seven duplicate amino acids, arginine (R)-595 through leucine(L)-601, in the juxtamembrane domain of the Flt3 protein (PMID: 11756186). R595_L601dup results in constitutive phosphorylation of Flt3, activation of Stat5 and Erk signaling, transformation of cells in culture, and induction of myeloproliferative disorder in mouse models (PMID: 18068628, PMID: 11756186).
FLT3 Y599_D600insGLYVDFREYEY insertion gain of function - predicted FLT3 Y599_D600insGLYVDFREYEY results in the insertion of 11 amino acids in the juxtamembrane domain of the Flt3 protein between amino acids 599 and 600 (PMID: 11756186). Y599_D600insGLYVDFREYEY results in transformation in cell culture (PMID: 11756186) and therefore, is predicted to lead to a gain of Flt3 protein function.
FLT3 Y599_E604dup duplication gain of function - predicted FLT3 Y599_E604dup indicates the insertion of six duplicate amino acids, tyrosine (Y)-599 through glutamic acid (E)-604, in the juxtamembrane domain of the Flt3 protein (PMID: 11756186). Y599_E604dup has not been biochemically characterized, but can be predicted to lead to activation of Flt3 based on the effects of other Flt3 internal tandem duplication (ITD) mutations (PMID: 12970773, PMID: 9737679, PMID: 11090077).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References