Abstract
Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) are influenced by sex, but little attention has been directed at untangling sex-related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk are generally associated with a male phenotype, the poor prognostic FLT3 internal tandem duplication (FLT3-ITD) mutation and co-mutations with NPM1 and DNMT3A 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 in four cohorts: Beat AML, LAML-TCGA and two independent HOVON/SAKK cohorts, comprising 1755 AML patients in total. We found prevalent sex-associated molecular differences. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3-ITDs were characterized by additional mutations in RNA splicing and epigenetic modifier genes. We observed diverging expression of multiple leukaemia-associated genes as well as discrepant ex vivo drug responses, suggestive of discrete functional properties. Importantly, significant prognostication was observed only in female FLT3-ITD-mutated AML. Thus, we suggest optimization of FLT3-ITD mutation status as a clinical tool in a sex-adjusted manner and hypothesize that prognostication, prediction and development of therapeutic strategies in AML could be improved by including sex-specific considerations.
| Original language | English |
|---|---|
| Pages (from-to) | 2285-2299 |
| Number of pages | 15 |
| Journal | Molecular Oncology |
| Volume | 15 |
| Issue number | 9 |
| Early online date | 8 Jun 2021 |
| DOIs | |
| Publication status | Published - 1 Sept 2021 |
Bibliographical note
Funding Information:We are grateful to all patients who have participated in the respective clinical trials, and all members and clinical investigators of the HOVON/SAKK collaboration, the Cancer Genome Atlas and in the preparation and publication of the Beat AML sample cohort. This study was supported by funding from the Norwegian Cancer Society with Solveig & Ole Lunds Legacy, ?yvinn M?lbach-Petersens Fund for Clinical Research and grant no 303445. Additionally, the study was funded through Helse Vest HF Health Trust, Grant Numbers: 911809, 911852, 912171, 240222 and 912308.
Funding Information:
We are grateful to all patients who have participated in the respective clinical trials, and all members and clinical investigators of the HOVON/SAKK collaboration, the Cancer Genome Atlas and in the preparation and publication of the Beat AML sample cohort. This study was supported by funding from the Norwegian Cancer Society with Solveig & Ole Lunds Legacy, Øyvinn Mølbach‐Petersens Fund for Clinical Research and grant no 303445. Additionally, the study was funded through Helse Vest HF Health Trust, Grant Numbers: 911809, 911852, 912171, 240222 and 912308.
Publisher Copyright:
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
