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Molecular Subtypes of Acute Myeloid Leukemia and the Prevalence of FLT3 Mutation
Anna Love, M.B.S., Ph.D.
AS EVINCED in the introduction, the four main leukemia types: AML, ALL, chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL) have a large array of molecular subtypes. While AML has fewer mutations per exome or genome compared to other cancer types, those mutations combine in such diverse and unique ways that heterogeneity and patient response are highly variable. 10 While characterizing all of the AML molecular subtypes has been a difficult undertaking, major advances in understanding the expansive landscape of AML allowed for the identification of new prognostic markers and help set the course for new molecularly targeted treatments. 11 Based on 200 mutational profiles from AML patients in The Cancer Genome Atlas (TCGA) project, 23 genes were found to be recurrently mutated and patients averaged 13 coding mutations. From TGCA, nearly all samples had at least one mutation from one of nine distinct functional gene categories. 10 The categories and rate of occurrence in TCGA cohort include: transcription factor fusions (18%), gene encoding nucleophosmin (NPM1) (27%), tumour-suppressor genes (16%), DNA methylation-associated genes (44%), signaling genes (such as FLT3) (59%), chromatinmodifying genes (30%), myeloid transcription factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). 12
Spliceosome-Complex Genes
Mutations in splicing genes SRSF2, U2AF1, ZRSR2, and SXF3B1 have been recognized in myelodysplastic syndromes (MDS), severe cases of which can become AML. 13 Mutated SRSF2 indicate shorter overall survival and more frequent AML progression, and has a high association with RUNX1, a myeloid transcription factor, gene mutation. 14
Myeloid Transcription Factor Mutations
Acute myeloid leukemia 1 (AML1) protein, also known as runt-related transcription factor 1 (RUNX1) or core-binding factor subunit alpha-2 (CBFA2), is a protein encoded by the RUNX1
gene. 15,16
RUNX1 chromosomal translocations are the most common aberrations found in acute leukemia. AML-1 is a critical regulator of hematopoietic cell development, and when these translocations are present cell production is disrupted. 15
RUNX1 mutations are frequently found in radiation-exposed patients with MDS/AML and is associated with poor prognosis. However, the presence of mutated CCAAT enhancerbinding protein alpha (CEBPA), another transcription factor-encoding gene, is associated with a more favorable prognosis for AML patients, indicated by longer remission duration and overall survival than AML patients without CEBPA mutation. 17
Nucleophosmin (NPM1) Status
AML-carrying nucleophosmin (NPM), a protein encoded by the NPM1 gene that can shuttle cargo from the nucleolus to the nucleoplasm. In a New England Journal of Medicine study, 35.2% of primary AML patients exhibited cytoplasmic accumulation of NPM, a result of NPM1 gene mutation. The presence of cytoplasmic NPM was associated with a normal karyotype and better patient response to induction chemotherapy. This study also reported a high frequency of FLT3-ITDs in CD34- and CD133-negative AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, which is associated with poor outcomes. 18
DNA Methylation-Related Genes DNA methylation is an epigenetic posttranslational modification that regulates gene expression and the production of blood cells.
Quizartinib is a small molecule receptor tyrosine kinase inhibitor for the treatment of acute myeloid
Many cancer types present with alterations in DNA methylation, which lead to genomic instability and aberrant gene expression. 19 Hypermethylated tumour suppressor genes become defective, generating a poor outcome. DNA methylation is considered an important marker for early diagnosis, prognosis, and therapeutic decision making in the treatment of AML. Approximately, 25% of AML patients present with a DNA methylation-related mutation. 20
Tumour Suppressor Genes
The most prevalent tumour suppressor gene across all cancers is TP53. Though its prevalence in AML is significantly lower than in other types of cancer, the presence of TP53 mutations indicates a high resistance to chemotherapy and high risk of relapse. Most AMLs display no genomic TP53 alterations and this may prove to be advantageous as new targeted therapies are developed capable of exploiting unaltered genes. 21
Chromatin-Modifying Genes
Genes responsible for stem cell development and myeloid/lymphoid cell lineage have been found to be fused to incorrect chromatinmodifying enzymes. 15 Additional sex combslike 1 (ASXL1) mutations are regularly found in MDS, AML, chronic myeloid leukemia, chronic myelomonocytic leukemia, and myeloproliferative neoplasms. ASXL1 interacts with retinoic acid receptors and is a putative driver of chromatin remodeling. 16
Cohesin-Complex Genes
The cohesin complex is a multiprotein ring that aligns and stabilizes replicated chromosomes prior to cell division. STAG2 mutations within the cohesin complex are frequently found in AML, as well as, in solid tumours and are found in Ewing’s Sarcoma, bladder cancer, and glioblastoma. 22
Signaling Genes
Wild-type FMS-like tyrosine kinase 3 (FLT3) receptors have been found at the mRNA and/ or protein level in 93% of AML patients, 87% of T-cell acute lymphoblastic leukemia, and nearly 100% of B-cell ALL patients. 23 Genotyping of colonies and relapse samples suggest that signaling gene mutations are a result of clonal interference, which is pervasive in cancers but has unclear mechanisms and prognostic impact. 24 Due to its mutational frequency, FLT3-targeted therapies are at the forefront of AML personalized treatment.
