GATA2 syndrome hematopoietic evolution. Somatic genetic alterations predict hematological progression in GATA2 deficiency

Germline GATA2 mutations predispose to myeloid malignancies resulting from the progressive acquisition of additional somatic mutations. Here we describe clinical and biological features of 78 GATA2 deficient patients. Hematopoietic stem and progenitor cell phenotypic characterization showed an exhaustion of myeloid progenitors. Somatic mutations in STAG2, ASXL1, SETBP1 genes, and cytogenetic abnormalities (monosomy 7, trisomy 8, der(1;7)) are frequent in patients with GATA2 germline mutations, when compared to patients with sporadic AML. Patients were classified into three hematopoietic stages based on bone marrow cytomorphology. No somatic additional mutations were detected in patients with normal bone marrow (stage 0), whereas clonal hematopoiesis mediated by STAG2 mutations was frequent in those with a hypocellular or myelodysplastic bone marrow (stage 1). Finally, SETBP1, RAS pathway genes and RUNX1 mutations were predominantly associated with leukemic transformation (stage 2), highlighting their implications in the transformation process. Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/hematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians for their management of patients, but also clarify the mechanism of leukemogenesis in germline GATA2 mutations.