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Ref Type Journal Article
PMID (33914060)
Authors Young DJ, Nguyen B, Zhu R, Seo J, Li L, Levis MJ, Pratz KW, Duffield AS, Small D
Title Deletions in FLT-3 juxtamembrane domain define a new class of pathogenic mutations: case report and systematic analysis.
Journal Vol Issue Date Pages Journal Short Title
Blood advances 5 9 2021 May 11 2285-2293 Blood Adv
URL
Abstract Text The FMS-like tyrosine kinase 3 (FLT-3) is the most frequently mutated gene in acute myeloid leukemia (AML), a high-risk feature, and now the target of tyrosine kinase inhibitors (TKIs), which are approved and in development. The most common mutation is the internal tandem duplication (ITD). We present a novel mutation, FLT-3/Q575Δ, identified in a patient with AML through next-generation sequencing (NGS). This mutation is activating, drives downstream signaling comparable to FLT-3/ITD, and can be targeted using available FLT-3 TKIs. We present the results of a systematic analysis that identified Y572Δ, E573Δ, and S574Δ as similarly activating and targetable deletions located in the FLT-3 juxtamembrane domain (JMD). These mutations target key residues in the JMD involved in the interactions within FLT-3 that regulate its activation. Our results suggest a new class of FLT-3 mutations that may have an impact on patient care and highlight the increasing importance of a systematic understanding of FLT-3 mutations other than ITD. It is likely that, as NGS becomes more commonly used in the diagnosis of patients with AML, these and other activating mutations will be discovered with increasing frequency.

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Molecular Profile Treatment Approach
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 E573del deletion gain of function FLT3 E573del results in the deletion of an amino acid in the juxtamembrane domain of the Flt3 protein at amino acid 573 (PMID: 14759363). E573del confers a gain of function to the Flt3 protein as demonstrated by activation of Stat5, Akt, and Erk1/2 signaling and IL3-independent growth in cultured cells (PMID: 33914060).
FLT3 Q575del deletion gain of function FLT3 Q575del results in the deletion of an amino acid in the juxtamembrane domain of the Flt3 protein at amino acid 575 (PMID: 14759363). Q575del confers a gain of function to the Flt3 protein as demonstrated by activation of Stat5, Akt, and Erk1/2 signaling and IL3-independent growth in cultured cells (PMID: 33914060).
FLT3 S574del deletion gain of function FLT3 S574del results in the deletion of an amino acid in the juxtamembrane domain of the Flt3 protein at amino acid 573 (PMID: 14759363). S574del confers a gain of function to the Flt3 protein as demonstrated by activation of Stat5, Akt, and Erk1/2 signaling and IL3-independent growth in cultured cells (PMID: 33914060).
FLT3 Y572del deletion gain of function FLT3 Y572del results in the deletion of an amino acid in the juxtamembrane domain of the Flt3 protein at amino acid 572 (PMID: 14759363). Y572del confers a gain of function to the Flt3 protein as demonstrated by activation of Stat5, Akt, and Erk1/2 signaling and IL3-independent growth in cultured cells (PMID: 33914060).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 Q575del hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) decreased downstream signaling and proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 Q575del hematologic cancer sensitive Tamatinib Preclinical - Cell culture Actionable In a preclinical study, Tamatinib (R406) decreased proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 Q575del hematologic cancer sensitive Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Vanflyta (quizartinib) decreased proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 Q575del hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) decreased downstream signaling and proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 S574del hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib (CP-868596) decreased proliferation in transformed cells expressing FLT3 S574del in culture (PMID: 33914060). 33914060
FLT3 Y572del hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) decreased proliferation in transformed cells expressing FLT3 Y572del in culture (PMID: 33914060). 33914060
FLT3 Q575del hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib (CP-868596) decreased proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 S574del hematologic cancer sensitive Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Vanflyta (quizartinib) decreased proliferation in transformed cells expressing FLT3 S574del in culture (PMID: 33914060). 33914060
FLT3 Y572del hematologic cancer sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) decreased proliferation in transformed cells expressing FLT3 Y572del in culture (PMID: 33914060). 33914060
FLT3 Q575del acute myeloid leukemia predicted - sensitive Cytarabine + Daunorubicin + Gilteritinib Case Reports/Case Series Actionable In a clinical case study, induction therapy with Cytosar-U (cytarabine) and Cerubidine (daunorubicin) combined with Xospata (gilteritinib) resulted in complete remission in a patient with acute myeloid leukemia harboring FLT3 Q575del (PMID: 33914060). 33914060
FLT3 E573del hematologic cancer sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) decreased proliferation in transformed cells expressing FLT3 E573del in culture (PMID: 33914060). 33914060
FLT3 S574del hematologic cancer sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) decreased proliferation in transformed cells expressing FLT3 S574del in culture (PMID: 33914060). 33914060
FLT3 Q575del hematologic cancer sensitive AG1295 Preclinical - Cell culture Actionable In a preclinical study, AG1295 decreased downstream signaling and proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 E573del hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) decreased proliferation in transformed cells expressing FLT3 E573del in culture (PMID: 33914060). 33914060
FLT3 Q575del hematologic cancer sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) decreased proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 Q575del hematologic cancer sensitive KW-2449 Preclinical - Cell culture Actionable In a preclinical study, KW-2449 decreased proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 Y572del hematologic cancer sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) decreased proliferation in transformed cells expressing FLT3 Y572del in culture (PMID: 33914060). 33914060
FLT3 Q575del hematologic cancer sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) decreased downstream signaling and proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 E573del hematologic cancer sensitive Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Vanflyta (quizartinib) decreased proliferation in transformed cells expressing FLT3 E573del in culture (PMID: 33914060). 33914060
FLT3 Y572del hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib (CP-868596) decreased proliferation in transformed cells expressing FLT3 Y572del in culture (PMID: 33914060). 33914060
FLT3 E573del hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib (CP-868596) decreased proliferation in transformed cells expressing FLT3 E573del in culture (PMID: 33914060). 33914060
FLT3 S574del hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) decreased proliferation in transformed cells expressing FLT3 S574del in culture (PMID: 33914060). 33914060
FLT3 S574del hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) decreased proliferation in transformed cells expressing FLT3 S574del in culture (PMID: 33914060). 33914060
FLT3 E573del hematologic cancer sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) decreased proliferation in transformed cells expressing FLT3 E573del in culture (PMID: 33914060). 33914060
FLT3 E573del hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) decreased proliferation in transformed cells expressing FLT3 E573del in culture (PMID: 33914060). 33914060
FLT3 Y572del hematologic cancer sensitive Lestaurtinib Preclinical - Cell culture Actionable In a preclinical study, Lestaurtinib (CEP-701) decreased proliferation in transformed cells expressing FLT3 Y572del in culture (PMID: 33914060). 33914060
FLT3 S574del hematologic cancer sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) decreased proliferation in transformed cells expressing FLT3 S574del in culture (PMID: 33914060). 33914060
FLT3 Q575del hematologic cancer sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) decreased proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 Q575del hematologic cancer sensitive Linifanib Preclinical - Cell culture Actionable In a preclinical study, Linifanib (ABT-869) decreased proliferation in transformed cells expressing FLT3 Q575del in culture (PMID: 33914060). 33914060
FLT3 Y572del hematologic cancer sensitive Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Vanflyta (quizartinib) decreased proliferation in transformed cells expressing FLT3 Y572del in culture (PMID: 33914060). 33914060