Biallelic disruption of DDX41 activity is associated with distinct genomic and immunophenotypic hallmarks in acute leukemia.

INTRODUCTION

Inherited mutations cause familial predisposition to hematologic malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with the majority of DDX41 mutated MDS/AMLs described to date harboring germline and co-occurring somatic variants. DDX41-AMLs were shown to share distinguishing clinical features such as a late AML onset and an indolent disease associated with a favorable outcome. However, genotype-phenotype correlation in DDX41-MDS/AMLs remain poorly understood.

METHODS

Here, we studied the genetic profile, bone marrow morphology and immunophenotype of 51 patients with DDX41 mutations. We further assessed the functional impact of ten previously uncharacterized variants of uncertain significance.

RESULTS

Our results demonstrate that MDS/AML cases harboring two variants share specific clinicopathologic hallmarks that are not seen in other patients with monoallelic related hematologic malignancies. We further showed that the features seen in these individuals with two variants were concordant with biallelic disruption.

DISCUSSION

Here, we expand on previous clinicopathologic findings on mutated hematologic malignancies. Functional analyses conducted in this study unraveled previously uncharacterized alleles and further illustrate the implication of biallelic disruption in the pathophysiology of this distinct AML entity.