IMPROVING IMPROVINGSURVIVAL SURVIVALRATES RATESIN INPATIENTS PATIENTSWITH WITHRELAPSED RELAPSEDAND ANDREFRACTORY REFRACTORYACUTE ACUTEMYELOID MYELOIDLEUKEMIA LEUKEMIA
Molecular Subtypes of Acute Myeloid Leukemia and the Prevalence of FLT3 Mutation Anna Love, M.B.S., Ph.D.
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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
S 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
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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.
