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

Abstract

GATA2, a zinc finger transcription factor predominantly expressed in hematopoietic cells, acts as an essential regulator of hematopoietic stem cell generation, survival and functionality. Loss and gain of GATA2 expression has been implicated in myelodysplastic syndrome and acute myeloid leukemia (AML) yet the precise biological impact of GATA2 expression on human AML cell fate decisions remains ambiguous. Herein, we performed large-scale bioinformatics that demonstrated relatively frequent GATA2 overexpression in AML patients as well as select human AML (or AML-like) cell lines. By using shRNAi to target GATA2 in these AML cell lines, and an AML cell line expressing normal levels of GATA2, we found that inhibition of GATA2 caused attenuated cell proliferation and enhanced apoptosis exclusively in AML cell lines that overexpress GATA2. We proceeded to pharmacologically inhibit GATA2 in concert with AML chemotherapeutics and found this augmented cell killing in AML cell lines that overexpress GATA2, but not in an AML cell line expressing normal levels of GATA2. These data indicate that inhibition of GATA2 enhances chemotherapy-mediated apoptosis in human AML cells overexpressing GATA2. Thus, we define novel insights into the oncogenic role of GATA2 in human AML cells and suggest the potential utilization of transient GATA2 therapeutic targeting in AML.

Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia

“…R software was used to analyze and produce data. Data processing, normalization, and analysis were described previously ( 97 ).…”

GATA2-Mediated Transcriptional Activation of Notch3 Promotes Pancreatic Cancer Liver Metastasis

“…Similarly, GATA2 inhibits the expression of MHC class I chain-related protein A/B (MICA/B) via binding their promoters, thereby mediating cancer cells to escape from immune surveillance ( Duan et al, 2019 ). By contrast, loss of GATA2 expression inhibits cancer proliferation and induces chemotherapy-mediated apoptosis in acute myeloid leukemia ( Menendez-Gonzalez et al, 2019 ). However, the roles of GATA2 in cancer metastasis has not been clearly illustrated.…”

Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells

“…The quest to develop more specific, targeted therapies for AML has been encumbered by 1) the genetic and epigenetic mutational complexity and heterogeneity observed in AML patients (Papaemmanuil et al, 2016), and 2) a subset of leukemia cells termed leukemia stem cells/initiating cells (LSCs), which are the root cause of AML disease, enabling AML cells to prosper, and which notably resist treatment by standard chemotherapy, ultimately causing relapse in AML (Bonnet and Dick 1997). We have addressed these issues by focusing on understanding the oncogenic function of haematopoietic specific transcription factor GATA2, which is overexpressed across several subtypes of AML and approximately 25% of all AML cases (Lahortiga et al, 2005;Menendez-Gonzalez et al, 2019b). In mouse models of AML driven by the co-expression of Meis1a and Hoxa9, we found that genetic deletion of Gata2 causes apoptosis of LSCs via reduction in the expression of anti-apoptotic factor BCL2 while also facilitating myeloid differentiation, overcoming the myeloid differentiation block normally observed in AML (Menendez-Gonzalez et al, 2019a).…”

“…In mouse models of AML driven by the co-expression of Meis1a and Hoxa9, we found that genetic deletion of Gata2 causes apoptosis of LSCs via reduction in the expression of anti-apoptotic factor BCL2 while also facilitating myeloid differentiation, overcoming the myeloid differentiation block normally observed in AML (Menendez-Gonzalez et al, 2019a). To further explore the potential for clinical targeting of GATA2 in AML, we reduced GATA2 expression using shRNAi in human AML cell lines overexpressing GATA2, which enhanced apoptosis and forestalled leukemic cell proliferation (Menendez-Gonzalez et al, 2019b). Of therapeutic relevance, a proteasome inhibitor (K7174) that inhibits GATA2 was able to successfully induce apoptosis in AML cell lines overexpressing GATA2 when combined with standard of care AML chemotherapy (Majik et al, 2012;Menendez-Gonzalez et al, 2019b).…”

“…To further explore the potential for clinical targeting of GATA2 in AML, we reduced GATA2 expression using shRNAi in human AML cell lines overexpressing GATA2, which enhanced apoptosis and forestalled leukemic cell proliferation (Menendez-Gonzalez et al, 2019b). Of therapeutic relevance, a proteasome inhibitor (K7174) that inhibits GATA2 was able to successfully induce apoptosis in AML cell lines overexpressing GATA2 when combined with standard of care AML chemotherapy (Majik et al, 2012;Menendez-Gonzalez et al, 2019b). These proof of principle data collectively suggest the potential of targeting GATA2 in AML and, more specifically, in AML LSCs.…”