Loss of Egr1, a human del5q gene, accelerates BCR-ABL driven chronic myelogenous leukemia

Abstract

There is substantial evidence that early growth response-1 (Egr1) gene, a zinc-finger transcription factor, behaves as a tumor suppressor in leukemia. This includes reports from this laboratory that constitutive Egr1 overrides leukemia conferred by deregulated c-Myc or E2F-1 in the M1 myeloid leukemic cell line by promoting differentiation. To investigate the effect of Egr1 on the initiation and progression of Chronic Myelogenous Leukemia (CML), lethally irradiated syngeneic wild type mice were reconstituted with bone marrow (BM) from either wild type or Egr1 null mice transduced with a 210-kD BCR-ABL-expressing MSCV-retrovirus (bone marrow transplantation {BMT}). Loss of Egr1 was observed to accelerate the development of BCR-ABL driven leukemia in recipient mice, resulting in the development of a more aggressive disease, a significantly shortened median survival time, and increased BCR-ABL expressing leukemic stem/progenitor cells (GFP+Lin-cKit+Sca+). Egr1 deficient progenitors expressing BCR-ABL exhibited decreased apoptosis, and increased cell viability and proliferation relative to WT counterparts. Secondary BMT of BCR-ABL BM revealed that loss of Egr1 resulted in enrichment of LSCs, consistent with shorter survival time and more aggressive disease of these mice compared to WT counterparts. Furthermore, serial re-plating colony assays indicated that loss of Egr1 increased self-renewal ability of BCR-ABL expressing BM. These novel findings on the tumor suppressor role of Egr1 in CML provide the impetus to study the effect of altering Egr1 expression in AML, where the overall five year survival rate remains low. The effect of loss of Egr1 in CML could reflect its established functions in normal hematopoiesis, maintaining quiescence of HSCs and driving terminal differentiation to the monocyte/macrophage lineage. Gain of function studies should validate these conclusions and provide further rationale for increased Egr1 as a therapeutic target in AML.

An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia

“…Finally, to identify putative BMI1-silenced BC tumor suppressor genes, we reexpressed a panel of BMI1-bound genes that were repressed in BC but upregulated by PTC209 exposure in primary CD34 1 BC cells (supplemental Figure 10A). Among these, we confirmed the growth-inhibiting properties of a previously described BC tumor suppressor gene, EGR1 92,93 (Figure 6A-B). Among 5 novel candidate genes, we found that NR4A2, a nuclear receptor transcription factor with no known role in leukemia, 94 was able to inhibit colony formation in BC cell lines (Figure 6C-D).…”

hsa-mir183/EGR1–mediated regulation of E2F1 is required for CML stem/progenitor cell survival

“…Indeed, recent evidence demonstrates that leukemia development is accelerated in the absence of EGR1 in a CML mouse model. 38 E2F1 upregulation was BCR-ABL1 kinase dependent and its inhibition led to a decrease in colony-forming potential, cellcycle arrest, and induction of p53-mediated cell death, suggesting the dependency of leukemic SPCs on E2F1.…”

“…[35][36][37] Furthermore, it has recently been shown that genetic deletion of Egr1 accelerates BCR-ABL1-driven CML. 38 Here, we identify a novel CML-specific pathway in which BCR-ABL1 protein kinase regulates hsa-mir183-mediated inhibition of EGR1 leading to upregulation of E2F1. In addition, we investigate the role that hsa-mir183/EGR1-mediated E2F1 expression plays in priming proliferation in CML SPCs.…”

miR‑let‑7c‑3p targeting on Egr‑1 contributes to the committed differentiation of leukemia cells into monocyte/macrophages

“…Some findings suggest that Egr-1 can reverse the disease progression of acute myeloid leukemia by regulating changes in the downstream target genes c-myc and E2F1 (57). In chronic myeloid leukemia, a decrease in Egr-1 leads to an increase in the number of leukemia stem cells in the blood, accelerating disease progression, whereas Egr-1 serves an important role in normal hematopoietic stem cell differentiation, quiescence and terminal differentiation of monocyte/macrophage cells (58). As early as the last century, some researchers identified Egr-1 as an important differentiation response gene during monocyte/macrophage development (59), it is greatly upregulated in HL-60 and U-937 leukemia cells following exposure to PMA.…”