Molecular Genetic Markers in Acute Myeloid Leukemia

Abstract

Genetics play an increasingly important role in the risk stratification and management of acute myeloid leukemia (AML) patients. Traditionally, AML classification and risk stratification relied on cytogenetic studies; however, molecular detection of gene mutations is playing an increasingly important role in classification, risk stratification, and management of AML. Molecular testing does not take the place of cytogenetic testing results, but plays a complementary role to help refine prognosis, especially within specific AML subgroups. With the exception of acute promyelocytic leukemia, AML therapy is not targeted but the intensity of therapy is driven by the prognostic subgroup. Many prognostic scoring systems classify patients into favorable, poor, or intermediate prognostic subgroups based on clinical and genetic features. Current standard of care combines cytogenetic results with targeted testing for mutations in FLT3, NPM1, CEBPA, and KIT to determine the prognostic subgroup. Other gene mutations have also been demonstrated to predict prognosis and may play a role in future risk stratification, although some of these have not been confirmed in multiple studies or established as standard of care. This paper will review the contribution of cytogenetic results to prognosis in AML and then will focus on molecular mutations that have a prognostic or possible therapeutic impact.

Characterization of CEBPA Mutations and Polymorphisms and their Prognostic Relevance in De Novo Acute Myeloid Leukemia Patients

“…In previous studies a favourable outcome for the CEBPA mutation has been reported. CEBPA mutations improve the prognosis of AML with normal cytogenetics from intermediate to favorable (Yohe, 2015). Present study also reveals a significant favorable impact for the mutated patients with respect to wild type in overall cases (P=0.028).…”

Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia

“…33 Notably, MP-A08 is known to be equally effective at inhibiting human and mouse sphingosine kinases. 33 This therapeutic response occurred in 2 independent AML samples, both with normal karyotype, carrying the FLT3-ITD mutation and either IDH1 or IDH2 mutations, a common occurrence in AML, 54 suggesting SPHK1-directed therapies may have utility across this spectrum of AML. Notably, cells from patient AML8, harboring the 11q23 MLL translocation, were nonresponsive to MP-A08 in vivo, consistent with our subsequent findings that SPHK1 inhibition in these cells did not result in loss of MCL1, a protein known to be critical for AML cell survival.…”

Unhealthy Stem Cells: When Health Conditions Upset Stem Cell Properties

“…Several types of leukemia have been identified, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL) and chronic myeloid leukemia (CML). The existence of LSCs was first described in AML [119] and many studies have identified mutations in different genes [reviewed in [120], and many other genes have been described in CML [121]. The existence of LSCs derived by malignant transformation of stem cells for is less clear for ALL, and instead it appears to be caused by a variety of mutated committed progenitors [122].…”