A. GATA2 deficiency and donor-derived leukemia. GATA2 deficiency is associated with germline predisposition to severe immunodeficiency and myelodysplastic syndrome / acute myeloid leukemia (MDS/AML). The prevelance of germline GATA2 mutations may be higher than initially expected as recent studies have shown that approximately 7% of pediatric/adolescent MDS (and 15% of pediatric MDS EB), harbor germline GATA2 mutations. We identified three families in which one or more members were diagnosed with MDS/AML and underwent hematopoietic stem cell transplantation (HSCT) using a healthy related donor in which both patient and donor unknowingly harbored germline mutations in GATA2. In all of the four cases the outcome was fatal resulting in donor-derived MDS/AML, poor engraftment and/or recurrent disease. Germline GATA2 mutations were identified after transplant. One of the cases occurred as recently as 2014, three years after the identification of germline GATA2 mutations and predisposition to MDS/AML. Germline mutations in GATA2 are associated with variable penetrance, variable age in onset of disease, variable phenotype and severity, which may hinder recognition of familial disease. In some families, it appears that a subset of individuals with the mutation may be clinically silent or asymptomatic well into late adulthood, while other members of the same family may develop severe disease early in life. In collaboration with Dr. Steven Holland, Dr. Dennis Hickstein and Dr. Neal Young we performed immunophenotypic and somatic mutation analyses on samples available from these families. The most important recommendation based on this study is that all pediatric, adolescent and young adults diagnosed with MDS/AML be tested for germline GATA2 mutations if a related family member will be used as a donor for HSCT. A manuscript reporting the findings was published in Blood in 2018. B. MicroRNA changes in MGUS. In an ongoing collaboration with Dr. Youn Shim and Dr. Robert Vogt at the CDC, Dr. Ola Landgren at MSKCC, and Dr. Joel Michalek at UTHSA we previously generated miRNA profiles of serum from Ranch Hand Air Force veterans who developed MGUS and age match veteran controls without MGUS. Bioinformatic and statistical analysis of the results in 2018 revealed age related changes in several miRNA in controls and cases over time, and differences in the pattern of changes in a subset of miRNA between the MGUS cases and controls. Additional studies are ongoing. C. RAS-associated Autoimmune Leukoproliferative Disorder (RALD) is a chronic indolent condition that typically presents in childhood with monocytosis, lymphocytosis, autoimmune phenomena, splenomegaly, and variable lymphadenopathy. RALD is characterized by somatic mutations in KRAS or NRAS in hematopoietic cells. Despite the indolent course of RALD, it shares some overlapping clinical features and similar genetic defects with Juvenile Myelomonocytic Leukemia (JMML), which is also characterized by underlying RAS-pathway mutations. The nature of RALD is controversial as some experts argue that RALD represents a form of JMML, while others view RALD as a benign disease. While malignant transformation to JMML or acute leukemia has not been observed in the large RALD cohort followed at NIH to date, we now have two patients who have developed lymphoma. In 2019, in collaboration with Dr. Koneti Rao, we continue to monitor RALD patients for signs of progressive disease. We are sorting peripheral blood samples into B-cells and myelomonocytic populations to evaluate presence of RAS mutations in specific lineages and are performing targetted sequencing to evaluate potential emerging somatic mutations that may herald transformation to JMML, lymphoma, or more aggressive disease. D. MicroRNA profiling of GATA2 deficiency associated MDS/AML. We previously identified significantly altered levels of FLT3 ligand, miR-181c and mir-424 in GATA2 deficiency. Ongoing functional studies continued in 2019 to elucidate relationships between GATA2, FLT3L, miR-181c and miR424. E. Immunophenotypic and morphologic analyses of rare diseases with bone marrow and peripheral blood pathology. Multiple collaborative research studies continued in 2018-2019 including studies related to acute myeloid leukemia, chronic lymphocytic leukemia, myeloma, autoinflammatory interferonopathies, IKAROS haploinsufficiency, paroxysmal nocturnal hemoglobinuria, aplastic anemia, CTLA4 deficiency, ADA2 deficiency, CANDLE syndrome, and severe combined immunodeficiency disorder.
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