GATA2 Related Conditions and Predisposition to Pediatric Myelodysplastic Syndromes

Abstract

Myelodysplastic syndromes (MDS) are hematopoietic disorders rare in childhood, often occurring in patients with inherited bone marrow failure syndromes or germinal predisposition syndromes. Among the latter, one of the most frequent involves the gene GATA binding protein 2 (GATA2), coding for a transcriptional regulator of hematopoiesis. The genetic lesion as well as the clinical phenotype are extremely variable; many patients present hematological malignancies, especially MDS with the possibility to evolve into acute myeloid leukemia. Variable immune dysfunction, especially resulting in B- and NK-cell lymphopenia, lead to severe infections, including generalized warts and mycobacterial infection. Defects of alveolar macrophages lead to pulmonary alveolar proteinosis through inadequate clearance of surfactant proteins. Currently, there are no clear guidelines for the monitoring and treatment of patients with GATA2 mutations. In patients with MDS, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT) that restores normal hematopoiesis preventing the progression to acute myeloid leukemia and clears long-standing infections. However, to date, the donor type, conditioning regimen, and the optimal time to proceed to HSCT, as well as the level of chimerism needed to reverse the phenotype, remain unclear highlighting the need for consensus guidelines.

Role of CBL Mutations in Cancer and Non-Malignant Phenotype

“…A similar prevalence of germline mutations in cancer-predisposing genes has been identified in children and adolescents with cancer [3]. In addition to providing important insights into diagnostic and prognostic information, the evaluation of non-tumor or germline material has provided novel information on previously unrecognized non-malignant clinical spectrum [4][5][6][7][8]. Casitas B lineage lymphoma (CBL) is a multifunctional gene codifying for a class of adaptor proteins (CBL family proteins) implicated in the regulation of signal transduction in many physiological and pathological processes.…”

GATA 2 Deficiency: Focus on Immune System Impairment

“…Although immunodeficiency represents one of the main features of the clinical picture, the high risk of developing myeloid neoplasms is the main sword hanging over the head of patients with GATA2 deficiency, presenting in more than 80% of patients by the age of 40 ( 41 ). The mechanism underlying this risk is likely to be found in the continuous stress, due to cytopenias and recurrent infections, to the malfunctioning bone marrow, leading to an accumulation of somatic mutations and selection of a clone with proliferative advantage in a predominantly hypocellular environment; ASXL1 alterations drive most frequently leukemogenic transformation ( 42 , 43 ).…”

“…Together with SAMD9/9L mutation, GATA2 germline mutation is one of the most common genetic cause of MDS, causing 15% of advanced forms and 7% of all primary MDS in childhood ( 44 , 45 ). Mirror wise, MDS is the commonest malignancy among this population, representing roughly 3/4 of neoplasms, followed by AML, that can evolve from MDS or be the initial presentation ( 23 , 41 , 44 ). Lymphoblastic acute leukemia (ALL), juvenile myelomonocytic leukemia (JMML), and aplastic anemia (AA) can also occur ( 23 , 41 , 44 ).…”

“…Mirror wise, MDS is the commonest malignancy among this population, representing roughly 3/4 of neoplasms, followed by AML, that can evolve from MDS or be the initial presentation ( 23 , 41 , 44 ). Lymphoblastic acute leukemia (ALL), juvenile myelomonocytic leukemia (JMML), and aplastic anemia (AA) can also occur ( 23 , 41 , 44 ). Cytogenetic aberrations are frequently identified in GATA2-related MDS: monosomy 7 or der(7; 1q) are the most common, found in about 41% of cases, followed by trisomy 8, identified in roughly 15% of cases among published studies ( 11 , 20 ); moreover, complex karyotypes are generally very rare, whereas del5q have never been described ( 11 , 20 ).…”

Genetic Predisposition to Myelodysplastic Syndromes: A Challenge for Adult Hematologists

“…GATA2 mutated patients were older at diagnosis and presented more often with monosomy 7 (identified in 70% of these patients) [ 31 ]. In patients with MDS, a GATA2 deficiency should be suspected in case of suggestive clinical features, such as monocytopenia, infection by atypical mycobacteria, recurrent HPV infections, lymphedema or monosomy 7 [ 31 , 32 ]. Screening tests searching for healthy carriers should be performed in families with a case of GATA2 deficiency; however, the best management for healthy carriers is not well established.…”