Changes

==Primary Author(s)*==

==Primary Author(s)*==

Dr Kay Weng Choy MBBS, BMedSci, FAACB, Monash Health

Kay Weng Choy, MBBS, Monash Medical Centre

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==Cancer Category/Type==

==Cancer Category/Type==

[[Acute myeloid leukemia (AML) and Related Precursor Neoplasms]]

[[HAEM4:Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms]]

[[HAEM5:Myeloid/lymphoid neoplasm with FLT3 rearrangement]]

 

''FLT3'' is a member of the type III receptor tyrosine kinase family that regulates hematopoiesis [1]. The receptor is activated by binding of the FLT3 ligand to the extracellular domain, which leads to homodimer formation in the plasma membrane and consequently autophosphorylation of tyrosine residues in the receptor; the activated receptor kinase then phosphorylates and activates multiple cytoplasmic effector molecules involved in proliferation and differentiation of hematopoietic cells in the bone marrow [2]. ''FLT3'' contains five functional domains: an immunoglobulin-like extracellular domain, a transmembrane domain, a juxtamembrane domain (JMD), an interrupted tyrosine kinase domain (TKD), and a small C-terminal domain [3].

''FLT3'' mutations occur in about one-third of patients with AML [3]. In-frame duplications of 3 to >400 base pairs, also known as internal tandem duplications (ITDs), are the most common mutations in ''FLT3'' and they occur in up to 30% of adult patients with ''de novo'' AML [3,4,5,6]. About 70% of ''FLT3''-ITDs occur in the JMD and about 30% in the TKD [3]. The JMD inhibits activation of the receptor by steric hindrance, preventing the TKD from assuming an active conformation; presence of an ITD causes loss of this inhibitory effect, resulting in activation of the TKD.

''FLT3'' mutations occur in about one-third of patients with AML [3]. In-frame duplications of 3 to >400 base pairs, also known as internal tandem duplications (ITDs), are the most common mutations in ''FLT3'' and they occur in up to 30% of adult patients with ''de novo'' AML [3,4,5,6]. About 70% of ''FLT3''-ITDs occur in the JMD and about 30% in the TKD [3]. The JMD inhibits activation of the receptor by steric hindrance, preventing the TKD from assuming an active conformation; presence of an ITD causes loss of this inhibitory effect, resulting in activation of the TKD.

''FLT3''-ITD and ''FLT3''-TKD mutations are common in patients with AML with normal karyotype but they can also be associated with abnormal karyotype, such as t(15;17)/PML-RARA and core binding factor (''CBF'') AML. ''FLT3''-ITD is frequently associated with t(6;9)(p23;q34.1) abnormalities [12]. The prognosis for patients with ''FLT3'' mutations can be affected by the presence or absence of additional mutations. Patients who are ''FLT3''-ITD negative (''FLT3''-ITD-) or ''FLT3''-ITD low and positive for nucleophosmin 1 mutations (NPM1+) have a “favorable” prognosis; patients who are FLT3-ITD- (or FLT3-ITDlow) with NPM1-WT have an intermediate prognosis [10]. On the other hand, patients who are FLT3-ITDhigh with NPM1-WT have a “poor” prognosis and are less likely to achieve complete remission (CR) with induction chemotherapy than patients with other ''FLT3''/''NPM1'' combinations [3,13].  

''FLT3'' is a member of the type III receptor tyrosine kinase family that regulates hematopoiesis [1]. The receptor is activated by binding of the FLT3 ligand to the extracellular domain, which leads to homodimer formation in the plasma membrane and consequently autophosphorylation of tyrosine residues in the receptor; the activated receptor kinase then phosphorylates and activates multiple cytoplasmic effector molecules involved in proliferation and differentiation of hematopoietic cells in the bone marrow [2]. ''FLT3'' contains five functional domains: an immunoglobulin-like extracellular domain, a transmembrane domain, a juxtamembrane domain (JMD), an interrupted tyrosine kinase domain (TKD), and a small C-terminal domain [3].

 

Allogeneic hematopoietic stem cell transplant (alloHSCT) is generally recommended for patients with ''FLT3''-ITD mutations in first complete remission (CR1), provided they are eligible for transplant therapy and have a suitable donor. Among patients with ''FL3''-ITD mutations in ''CR1'', those who undergo alloHSCT have significantly better outcomes (e.g., prolonged survival and decreased risk of relapse) than those who receive chemotherapy alone. Despite this, ''FLT3''-ITD remains a poor prognostic factor (high relapse rate and short relapse-free and overall survival) after alloHSCT and chemotherapy. Patients with ''FLT3''-ITD AML may benefit from the use of ''FLT3'' tyrosine kinase inhibitors as maintenance therapy to prevent relapse following alloHSCT.

Given its prognostic and predictive values, it is argued that ''FLT3'' testing should be performed in all AMLs regardless of cytogenetics [3]. If the ''FLT3''-ITD-to-WT allelic ratio is used for risk stratification, harmonisation of ''FLT3'' testing is essential to ensure that comparable results are achieved [3].

==Common Alteration Types==

==Common Alteration Types==

In-frame duplications of 3 to >400 base pairs, also known as internal tandem duplications (ITDs), are the most common mutations in ''FLT3'' and they occur in up to 30% of adult patients with ''de novo'' AML [3,4,5,6]. About 70% of ''FLT3''-ITDs occur in the JMD and about 30% in the TKD. See Figure in [3].

In-frame duplications of 3 to >400 base pairs, also known as internal tandem duplications (ITDs), are the most common mutations in ''FLT3'' and they occur in up to 30% of adult patients with ''de novo'' AML [3,4,5,6]. About 70% of ''FLT3''-ITDs occur in the JMD and about 30% in the TKD. See Figure in [3]. The second most common type of ''FLT3'' mutations in AML are those within the TKD (occurring in up to 14% of adult patients with AML) [3]. The majority are point mutations within the activation loop (e.g., residues D835, I836, Y842) of the TKD2, and within the TKD1 (e.g., residues N676, F691) [3,7]; activating mutations caused by insertions (e.g., insertion of glycine and serine between residues S840 and N841) and deletions have also been found in TKD [3]. Additional ''FLT3'' point mutations that have been found in patients with AML include mutations within the extracellular domain (e.g. T167, V194, D324, Y364, and V491), transmembrane domain (e.g., I548, V557), JMD (e.g., V579, E598), TKD1 (e.g., A680, M737), and TKD2 (e.g., V816, A814, T784). See Figure in [3].

 

The second most common type of ''FLT3'' mutations in AML are those within the TKD (occurring in up to 14% of adult patients with AML) [3]. The majority are point mutations within the activation loop (e.g., residues D835, I836, Y842) of the TKD2, and within the TKD1 (e.g., residues N676, F691) [3,11]; activating mutations caused by insertions (e.g., insertion of glycine and serine between residues S840 and N841) and deletions have also been found in TKD [3].

 

Additional ''FLT3'' point mutations that have been found in patients with AML include mutations within the extracellular domain (e.g. T167, V194, D324, Y364, and V491), transmembrane domain (e.g., I548, V557), JMD (e.g., V579, E598), TKD1 (e.g., A680, M737), and TKD2 (e.g., V816, A814, T784). See Figure in [3].

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! Copy Number Loss   !! Copy Number Gain   !! LOH   !!   Loss-of-Function Mutation   !! Gain-of-Function Mutation !! Translocation/Fusion  

!Copy Number Loss!!Copy Number Gain!!LOH!!Loss-of-Function Mutation!!Gain-of-Function Mutation!!Translocation/Fusion

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==Internal Pages==

==Internal Pages==

==External Links==

==External Links==

6. Patel JP, et al., (2012). Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366(12):1079-1089. PMID 22417203.

6. Patel JP, et al., (2012). Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366(12):1079-1089. PMID 22417203.

7. Thiede C, et al., (2002). Analysis of FLT3- activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99(12):4326-4335. PMID 12036858.

7. Smith CC, et al., (2012). Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485:260-263. PMID 22504184.

8. Pratcorona M, et al, (2002). Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood 121:2734-2738. PMID 23377436.

 

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

9. Gale RE, et al., (2008). The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111(5):2776-2784. PMID 17957027.

 

10. Dohner H, et al., (2017). Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424-447. PMID 27895058.

11. Smith CC, et al., (2012). Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485:260-263. PMID 22504184.

[[Category:Cancer Genes F]]

 

 

13. Walter RB, et al., (2015). Resistance prediction in AML: analysis of 4601 patients from MRC/ NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center. Leukemia 29(2):312-320. PMID 255113226.