Reference Detail

Ref Type

Journal Article

PMID

(37246158)

Authors

Ge SS, Qiu QC, Dai HP, Shen XD, Wu TM, Du JH, Wan CL, Shen HJ, Wu DP, Xue SL, Liu SB

Title

Mutation spectrum of FLT3 and significance of non-canonical FLT3 mutations in haematological malignancy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
British journal of haematology	202	3	2023 Aug	539-549	Br J Haematol

URL

Abstract Text

Fms-like tyrosine kinase 3 (FLT3) is frequently mutated in haematological malignancies. Although canonical FLT3 mutations including internal tandem duplications (ITDs) and tyrosine kinase domains (TKDs) have been extensively studied, little is known about the clinical significance of non-canonical FLT3 mutations. Here, we first profiled the spectrum of FLT3 mutations in 869 consecutively newly diagnosed acute myeloid leukaemia (AML), myelodysplastic syndrome and acute lymphoblastic leukaemia patients. Our results showed four types of non-canonical FLT3 mutations depending on the affected protein structure: namely non-canonical point mutations (NCPMs) (19.2%), deletion (0.7%), frameshift (0.8%) and ITD outside the juxtamembrane domain (JMD) and TKD1 regions (0.5%). Furthermore, we found that the survival of patients with high-frequency (>1%) FLT3-NCPM in AML was comparable to those with canonical TKD. In vitro studies using seven representative FLT3-deletion or frameshift mutant constructs showed that the deletion mutants of TKD1 and the FLT3-ITD mutant of TKD2 had significantly higher kinase activity than wild-type FLT3, whereas the deletion mutants of JMD had phosphorylation levels comparable with wild-type FLT3. All tested deletion mutations and ITD were sensitive to AC220 and sorafenib. Collectively, these data enrich our understanding of FLT3 non-canonical mutations in haematological malignancies. Our results may also facilitate prognostic stratification and targeted therapy of AML with FLT3 non-canonical mutations.

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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
FLT3	D586_D593delinsGG	indel	unknown	FLT3 D586_D593delinsGG results in a deletion of eight amino acids in the juxtamembrane domain of the Flt3 protein from amino acids 586 to 593, combined with the insertion of two glycines (G) at the same site (PMID: 37246158). D586_D593delinsGG results in Flt3 phosphorylation similar to wild-type Flt3 in culture (PMID: 37246158), but has not been fully biochemically characterized and therefore, its effect on Flt3 protein function is unknown.
FLT3	F590_D593delinsGP	indel	unknown	FLT3 F590_D593delinsGP 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 glycine (G) and a proline (P) at the same site (PMID: 37246158). F590_D593delinsGP results in Flt3 phosphorylation similar to wild-type Flt3 in culture (PMID: 37246158), but has not been fully biochemically characterized and therefore, its effect on Flt3 protein function is unknown.
FLT3	K614_G617del	deletion	gain of function - predicted	FLT3 K614_G617del results in the deletion of four amino acids in the protein kinase domain of the Flt3 protein from amino acids 614 to 617 (UniProt.org). K614_G617del results in increased Flt3 phosphorylation in culture (PMID: 37246158), and therefore, is predicted to lead to a gain of Flt3 protein function.
FLT3	Q577_Y589delinsPSD	indel	unknown	FLT3 Q577_Y589delinsPSD results in a deletion of 13 amino acids in the juxtamembrane domain of the Flt3 protein from amino acids 577 to 589, combined with the insertion of three amino acids at the same site (PMID: 37246158). Q577_Y589delinsPSD results in Flt3 phosphorylation similar to wild-type Flt3 in culture (PMID: 37246158), but has not been fully biochemically characterized and therefore, its effect on Flt3 protein function is unknown.
FLT3	S941_F942insRVS	insertion	gain of function - predicted	FLT3 S941_F942insRVS results in the insertion of three amino acids in the protein kinase domain of the Flt3 protein between amino acids 941 and 942 (UniProt.org). S941_F942insRVS results in increased Flt3 phosphorylation in culture (PMID: 37246158), and therefore, is predicted to lead to a gain of Flt3 protein function.
FLT3	Y589_D593del	deletion	unknown	FLT3 Y589_D593del results in the deletion of five amino acids in the juxtamembrane domain of the Flt3 protein from amino acids 589 to 593 (PMID: 37246158). Y589_D593del results in Flt3 phosphorylation similar to wild-type Flt3 in culture (PMID: 37246158), but has not been fully biochemically characterized and therefore, its effect on Flt3 protein function is unknown.
FLT3	Y591*	nonsense	loss of function - predicted	FLT3 Y591* results in a premature truncation of the Flt3 protein at amino acid 591 of 993 (UniProt.org). Y591* results in loss of kinase activity in culture (PMID: 37246158), and therefore, is predicted to lead to a loss of Flt3 protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 Q577_Y589delinsPSD	hematologic cancer	predicted - sensitive	Sorafenib	Preclinical - Biochemical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited Flt3 phosphorylation in cells expressing FLT3 Q577_Y589delinsPSD in culture (PMID: 37246158).	37246158
FLT3 D586_D593delinsGG	hematologic cancer	predicted - sensitive	Sorafenib	Preclinical - Biochemical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited Flt3 phosphorylation in cells expressing FLT3 D586_D593delinsGG in culture (PMID: 37246158).	37246158
FLT3 S941_F942insRVS	hematologic cancer	predicted - sensitive	Quizartinib	Preclinical - Biochemical	Actionable	In a preclinical study, Vanflyta (quizartinib) inhibited Flt3 phosphorylation in cells expressing FLT3 S941_F942insRVS in culture (PMID: 37246158).	37246158
FLT3 D586_D593delinsGG	hematologic cancer	predicted - sensitive	Quizartinib	Preclinical - Biochemical	Actionable	In a preclinical study, Vanflyta (quizartinib) inhibited Flt3 phosphorylation in cells expressing FLT3 D586_D593delinsGG in culture (PMID: 37246158).	37246158
FLT3 S941_F942insRVS	hematologic cancer	predicted - sensitive	Sorafenib	Preclinical - Biochemical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited Flt3 phosphorylation in cells expressing FLT3 S941_F942insRVS in culture (PMID: 37246158).	37246158
FLT3 Q577_Y589delinsPSD	hematologic cancer	predicted - sensitive	Quizartinib	Preclinical - Biochemical	Actionable	In a preclinical study, Vanflyta (quizartinib) inhibited Flt3 phosphorylation in cells expressing FLT3 Q577_Y589delinsPSD in culture (PMID: 37246158).	37246158
FLT3 K614_G617del	hematologic cancer	predicted - sensitive	Sorafenib	Preclinical - Biochemical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited Flt3 phosphorylation in cells expressing FLT3 K614_G617del in culture (PMID: 37246158).	37246158
FLT3 F590_D593delinsGP	hematologic cancer	predicted - sensitive	Sorafenib	Preclinical - Biochemical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited Flt3 phosphorylation in cells expressing FLT3 F590_D593delinsGP in culture (PMID: 37246158).	37246158
FLT3 F590_D593delinsGP	hematologic cancer	predicted - sensitive	Quizartinib	Preclinical - Biochemical	Actionable	In a preclinical study, Vanflyta (quizartinib) inhibited Flt3 phosphorylation in cells expressing FLT3 F590_D593delinsGP in culture (PMID: 37246158).	37246158
FLT3 K614_G617del	hematologic cancer	predicted - sensitive	Quizartinib	Preclinical - Biochemical	Actionable	In a preclinical study, Vanflyta (quizartinib) inhibited Flt3 phosphorylation in cells expressing FLT3 K614_G617del in culture (PMID: 37246158).	37246158