GATA1, GATA2, and TAL1 Regulate the Expression of Neurotrophic Receptor Tyrosine Kinase in Leukemia Cells

Abstract

Introduction Acute myeloid leukemia (AML) is a heterogeneous disease with poor overall survival and a high relapse rate. Transcription factors GATA1, GATA2, and TAL1 are key regulators of hematopoietic gene expression during normal embryonic and adult blood cell differentiation. Still, their roles in the regulation of cancer-specific genes during AML progression and therapy response remain unclear. Aims: Here, we aimed at the description of transcriptomic signatures of GATA1, GATA2, and TAL1 and identification of novel therapeutic targets in AML. Methods By the lentiviral transduction we have obtained leukemia (HL-60, Kasumi-1, THP-1) and neuroblastoma (SH-SY5Y) cell lines with overexpression of GATA1 and GATA2. Confocal microscopy was used to detect TrkA protein localization in cells. By qRT-PCR, we measured the expression of genes coding GATA1, GATA2, TAL1, and TrkA at mRNA levels. We used 5-azacytidine (5-aza) to induce changes in gene expression in leukemia cells. Cell viability was measured by trypan blue exclusion in the Neubauer chamber. Results First, we performed extensive data mining: analysis of publicly available transcriptome analysis data of 422 AML patients revealed genes differentially expressed (DEGs) with GATA1, GATA2, and TAL1. We found 125 genes common for GATA1, GATA2, and TAL1 including NTRK1 (encoding TrkA protein). Notably, by k-means clustering, we showed that patients with the induced level of GATA/TAL DEGs have poor overall survival. Previously we showed that leukemia cells have specific intracellular localization of TrkA protein. Ectopic expression of GATA1 and GATA2 in AML cells induced NTRK1 expression at mRNA and protein levels. 5-aza treatment of HL-60 cells resulted in the upregulation of GATA1, TAL1, and NTRK1 at mRNA and protein levels. Also, recombinant NGF (TrkA ligand) was able to rescue AML cells from 5-aza induced death. Conclusions Our data provide a novel mechanism of the GATA1, GATA2, and TAL1 involvement in AML progression. We show that NTRK1 expression is regulated by GATA1, GATA2, and TAL1 in leukemia but not in neuroblastoma cells. Our findings suggest the existence of GATA1, GATA2, and TAL1-driven control of non-hematopoietic genes in AML cells.