High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia

Abstract

Key Points• Mutations of key transcription factor in myeloid malignancies.Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reported GATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome. (Blood. 2013;121(5):822-829)

Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome

“…Neutropenia is a frequent finding in GATA-2-deficient patients, and it contributes to their immunodeficiency symptoms. 29,30 A study by Pasquet et al identified GATA-2-deficient patients in the cohort based on neutropenia. 30 Nearly normal ANC values were present only in UPN5 and UPN7, which was likely related to longterm use of corticosteroids due to lung disease.…”

“…29,30 A study by Pasquet et al identified GATA-2-deficient patients in the cohort based on neutropenia. 30 Nearly normal ANC values were present only in UPN5 and UPN7, which was likely related to longterm use of corticosteroids due to lung disease. Relative Tcell counts were increased in GATA-2-deficient patients in PB and BM.…”

Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes

“…27,28 Furthermore, indications for HSCT appear appropriate in patients with neutropenia dependent on chronically high doses of G-CSF (at least 10 μg/kg/day for at least 3 months per year), regarding the potential but not yet proven higher risk of clonal evolution, 29 and for patients with recurrent bacterial infections from a matched family donor. 29 Moreover, GATA2 mutations have been recently identified as a cause of mild congenital neutropenia associated with a high risk of leukemic transformation usually refractory to chemotherapy; 30 as such, the panel of experts agrees that HSCT might be considered if a matched donor is identified.…”

Heterogeneity of GATA2-related myeloid neoplasms

“…The analysis of patients enrolled in the French Severe Chronic Neutropenia Registry identified 7 pedigrees with germline GATA2 mutations who presented with mild chronic neutropenia associated with immunodeficiency and subsequent MDS evolution [38].…”