Two effects of GATA2 enhancer repositioning by 3q chromosomal rearrangements

AbstractChromosomal inversion and translocation between 3q21 and 3q26 [inv (3)(q21.3q26.2) and t(3;3)(q21.3;q26.2), respectively] give rise to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), which have poor prognoses. The chromosomal rearrangements reposition aGATA2 distal hematopoietic enhancer from the original 3q21 locus to theEVI1 (also known asMECOM) locus on 3q26. Therefore, theGATA2 enhancer from one of twoGATA2 alleles drivesEVI1 gene expression in hematopoietic stem and progenitor cells, which promotes the accumulation of abnormal progenitors and induces leukemogenesis. On the other hand, one allele of theGATA2 gene loses its enhancer, which results in reducedGATA2 expression. TheGATA2 gene encodes a transcription factor critical for the generation and maintenance of hematopoietic stem and progenitor cells.GATA2 haploinsufficiency has been known to cause immunodeficiency and myeloid leukemia. Notably, reducedGATA2 expression suppresses the differentiation but promotes the proliferation ofEVI1‐expressing leukemic cells, which acceleratesEVI1‐driven leukemogenesis. A series of studies have shown that theGATA2 enhancer repositioning caused by the chromosomal rearrangements between 3q21 and 3q26 provokes misexpression of both theEVI1 andGATA2 genes and that these two effects coordinately elicit high ‐risk leukemia.
Source: IUBMB Life - Category: Research Authors: Tags: CRITICAL REVIEW Source Type: research