Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis. Issue 9 (20th June 2021)

• Record Type: Journal Article
• Authors: Hellesøy, Monica; Engen, Caroline; Grob, Tim; Löwenberg, Bob; Valk, Peter J. M.; Gjertsen, Bjørn T.
• Is Part Of: Molecular oncology. Volume 15:Issue 9(2021)
• Page Start: 2285
• Page End: 2299
• Publication Date: 2021-06-20
• Subjects: acute myeloid leukaemia -- context‐dependency -- FLT3 -- FLT3‐ITD -- sex disparity; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.13035
• Languages: English
• ISSNs: 1574-7891

Abstract

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. Abstract : Internal tandem duplications (ITDs) in the FMS‐like tyrosine kinase 3 ( FLT3 ) gene are linked to poor prognosis in acute myeloid leukaemia (AML). Here, we investigated sex‐related differences in mutation, gene expression and drug sensitivity profiles in FLT3 ‐ITD‐mutated AML. We demonstrated significant sex‐associated molecular and functional differences, and surprisingly identified significant prognostication related to FLT3 ‐ITD only in female AML patients.