Modeling clonal hematopoietic disorders in gata2 heterozygosity using color-barcoding and mosaic mutagenesis in zebrafish
EvansMDS Young Investigator Award
Over the past decade our understanding of clonal myeloid disorders has opened a new gateway to tackling this group of malignancies, which have remained immune to the advancement of various new treatment modalities. Discoveries of genetic predisposition syndromes showed that hematologic malignancies, like many solid tumors, also can be associated with germline mutations, and that individuals with strong family history should be tested and followed closely for emergence of disease. The majority of the genes described in germline predisposition syndromes have been implicated in “de novo” MDS or AML, suggesting a common pathophysiology. Thus insights gained from research in MDS initiation in predisposition syndromes, a rare but critical group of diseases affecting patients of all ages, will most readily be translated to a larger population of adult patients suffering from MDS. My clinical interests in bone marrow failure syndromes, MDS/AML predisposition syndromes and the genetics of leukemia pathogenesis have further solidified my commitment to investigations in these fields.
Germline mutations in GATA2 that result in haploinsufficiency have an increased life-time risk of developing MDS and secondary AML. Clinical evidence in other germline MDS/AML predisposition syndromes, such as FPD/AML associated with RUNX1 mutations, has suggested the presence of a clonal hematopoiesis in asymptomatic individuals with mutations associated with de-novo MDS. Thus premalignant clonal hematopoiesis is potentially an important early step in the leukemogenesis in these syndromes. The exact role of these somatic mutations is unclear. I propose that, unlike in age related clonal hematopoiesis where the mutant clones may persist for decades without progressing into a malignancy, the abnormal clones have a much higher risk of malignant transformation in predisposition syndromes.
I plan to evaluate the clonal architecture at various ages in gata2 heterozygous fish using the myeloid output of color-barcoded stem cell population, and construct the clonal dynamics using the nucleated erythroid output in peripheral blood by serial sampling. Gata2 heterozygous mutant line recapitulates aspects of baseline adult hematopoiesis described in human patients, such as myelocytopenia, and will be used for understanding the developmental hematopoietic changes that may influence the properties of HSPCs and the risk of leukemogenesis later in life.