Sex disparity in acute myeloid leukemia – evidence from a study of FLT3-ITD mutated patients

Abstract

Little attention has been directed at untangling sex-related molecular and phenotypic differences in AML. While increased incidence and poor risk is generally associated with a male phenotype, FLT3-ITD, NPM1 and DNMT3A mutations are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3-ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity responses in four cohorts: the Beat AML cohort, the LAML-TCGA cohort and two independent HOVON/SAKK clinical trial-associated cohorts, comprising a total of 1755 AML patients. We found that sex-associated molecular differences were prevalent in FLT3-ITD mutated AML. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3-ITDs were characterised by additional mutations in genes involved in RNA splicing and epigenetic modification. Female and male FLT3-ITD mutated AML had diverging expression of multiple leukemia-associated genes, as well as discrepant ex vivo drug-responses, suggestive of discrete functional properties. Surprisingly, we found significant prognostication of FLT3-ITD only in female patients. Thus, we suggest optimisation of FLT3-ITD mutation status as a clinical tool in a sex-adjusted manner. We further hypothesize that prognostication, prediction and development of therapeutic strategies in AML can be improved by including sex-specific considerations.

FLT3‐ITD mutations in acute myeloid leukaemia – molecular characteristics, distribution and numerical variation

“…Of note, it was recently reported that risk-adapted treatment strategies in AML appear to have eliminated the poor risk association with FLT3-ITD [72]. We have confirmed this observation in the HOVON cohorts in a separate study; FLT3-ITD mutated patients in C1 had a significantly worse outcome compared to patients with FLT3wt, while there was no difference in overall survival between FLT3wt and FLT3-ITD in C2 [73]. Interestingly, in the present study we still identified a poor risk association with high mutational burden within the FLT3-ITD mutated subgroup of this cohort.…”

Sex-Related Differences in Chronic Myeloid Neoplasms: From the Clinical Observation to the Underlying Biology

“…The higher incidence of “pre-leukemic” mutations in men with AML was also highlighted by Metzeler et al who showed that mutations in RUNX1 , ASXL1 , SRSF2 , STAG2 , and BCOR genes were more prevalent in men compared to women in a cohort of 664 AML patients [ 33 ]. Finally, Engen et al reported in a preprint article that men with FLT3-ITD mutated AML have higher incidence of RUNX1 , ZRSR2 , SRSF2 , U2AF1 , ASXL1 and EZH2 mutations [ 34 ]. These results indicate a male predilection for mutations that have been reported to drive the progression of chronic myeloid neoplasms and their transformation to AML.…”

Evaluation the role of MicroRNAs in diagnosis and prognosis of acute myeloid leukemia

“…In the current study the age of patients distribution between 18-66 years, that may be related to the disease genes and some molecular features, that was most pronounced in the AML patients (Lindsley et al,2015). The age distribution by sex of leukemia patients, which is characterized by demography, indicates an important influence of age composition, and this can make age-matching the optimal condition for comparison (Engen et. al.,2020).…”