GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

Abstract

Drug resistance constitutes one of the main obstacles for clinical recovery of acute myeloid leukemia (AML) patients. Therefore, the treatment of AML requires new strategies, such as adding a third drug. To address whether GATA2 could act as a regulator of chemotherapy resistance in human leukemia cells, we observed KG1a cells and clinical patients’ AML cells with a classic drug (Cerubidine) and Gefitinib. After utilizing chemotherapy, the expression of GATA2 and its target genes (EVI, SCL and WT1) in surviving AML cells and KG1a cells were significantly enhanced to double and quadrupled compared to its original level respectively. Furthermore, with continuous chemotherapeutics, AML cells with GATA2 knockdown or treated with GATA2 inhibitor (K1747) almost eliminated with dramatically reduced expression of WT1, SCL, EVI, and significantly increased apoptotic population. Therefore, we propose that reducing GATA2 expression or inhibition of its transcription activity can relieve the drug resistance of acute myeloid leukemia cells and it would be helpful for eliminating the leukemia cells in patients.

Inhibition of GATA2 restrains cell proliferation and enhances apoptosis and chemotherapy mediated apoptosis in human GATA2 overexpressing AML cells

“…This inference is consistent with independent observations in the GATA2 overexpressing AML cell line KG-1 (Fig. 1E and 23 ). Yet GATA2 inhibition did not impact NOMO1 cells, which exhibit normal GATA2 expression.…”

“…Alternatively, as opposed to directly targeting GATA2, it may feasible to therapeutically target the GATA2 transcriptional network in these AML settings. Given that relative GATA2 expression increases in AML patients after chemotherapy 23 , beneficiaries of this therapy could extend beyond those patients who overexpress GATA2 at diagnosis. GATA2 mediated therapeutic strategies should also focus on human AML leukemic stem cells, where GATA2 expression is up-regulated 24 and where inducing cell death would be an attractive strategy to eliminate the provenance of leukemic cell growth.…”

GATA2 regulates the erythropoietin receptor in t(12;21) ALL

“…Following chemotherapy GATA2 was found to be normalized in patients in complete remission but remained high in those with resistant disease [ 23 ]. Recently it has been reported that reduction of GATA2 by shRNA or the inhibitor K7174 sensitizes KG1a acute myeloid leukemia cells to chemotherapy [ 24 ], suggesting that suppression of GATA2 expression or inhibition of its transcriptional activity may have potential as an ancillary therapy in AML.…”

Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

“…These prominently include aberrant splicing due to intron retention across several introns of BMI1, a gene known to be required for leukemogenesis that was also identified as a direct RBM39 mRNA-binding target by our eCLIP sequencing (eCLIP-seq). Additionally, GATA2, an essential hematopoietic factor involved in maintaining AML transcriptional homeostasis, was aberrantly spliced upon RBM39 loss (Katsumura et al, 2016;Yang et al, 2017) ( Figure 4I). The unannotated splicing changes observed in BMI1 and GATA2 upon RBM39 depletion are predicted to result in mRNAs that would be subjected to nonsense-mediated decay (NMD).…”