Stress Response Gene Egr-1 As Tumor Suppressor in BCR-ABL Mediated Leukemia
Authors: Maifrede Silvia , Liebermann Dan , Hoffman Barbara 
Published: October 2019

Abstract 33

Chronic Myelogenous Leukemia (CML) is a disease resulting from the neoplastic transformation of hematopoietic stem cells (HSC) with the BCR-ABL oncogene. The BCR-ABL protein is a constitutively active tyrosine kinase, which promotes cell survival and proliferation by means of diverse intracellular signaling pathways, thereby being the culprit for malignant transformation. In the late 1990s a Tyrosine Kinase Inhibitor (TKI), imatinib mesylate (Gleevec, Novartis) started to be effectively used on CML patients. However, imatinib, therapy suppresses rather than eliminates the disease, and resistance to imatinib has been described. Thus there is a high priority to enhance our understanding of how BCR/ABL subverts normal hematopoiesis and to identify novel targets for therapy. The transcription factor early growth response 1 (Egr-1) was identified as a macrophage differentiation primary response gene, shown to be essential for and to restrict differentiation along the macrophage lineage. There's evidence consistent with Egr-1 behaving as a tumor suppressor of leukemia, both in vivo and in vitro, including (1) loss of Egr-1 associated with treatment derived AMLs; (2) deregulated Egr-1 overriding blocks in myeloid differentiation, and (3) haplo-insufficiency of Egr-1 in mice leading to increased development of myeloid disorders following treatment with the potent DNA alkylating agent, N- ethyl-nitrosourea (ENU). Therefore, we chose to investigate if Egr-1 can act as a suppressor of BCR-ABL driven leukemia. To assess the effect of Egr-1 on BCR-ABL driven leukemia, lethally irradiated syngeneic wild type mice were reconstituted with bone marrow (BM) from either wild type or Egr-1 null mice transduced with a 210-kD BCR-ABL-expressing MSCV-retrovirus (bone marrow transplantation {BMT}). It was observed that loss of Egr-1 accelerated the development of BCR-ABL driven leukemia in recipient mice. Furthermore, we investigated the stem cell compartment of both Egr-1 WT and Egr-1−/− BM, by determining the percentage of stem cells (Lin−Sca+c-Kit+, LSK), before infection with BCR-ABL; no statistically significant difference in the percentage of LSK cells was observed between Egr-1 WT and Egr-1−/− BM. Thus, the BM stem cell compartment of the Egr-1−/− mice does not offer a quantitiative advantage to justify the faster development of leukemia compared to Egr-1 WT mice. Furthermore, when BM of transplanted mice was analyzed we observed an increased population of lineage negative cells in Egr-1−/− BCR-ABL recipients when compared to animals transplanted with WT BCR-ABL BM, consistent with more rapid development of disease. Preliminary results from serial BMT has shown that Egr-1−/− BCR-ABL BM has an increased leukemic burden when compared to the WT counterpart. Additional data from our animal model, as well as analysis of human leukemia samples will be presented, further corroborating that Egr-1 functions as a suppressor of BCR-ABL driven CML. These data could result in novel targets for diagnosis, prognosis, and targeted therapeutics for CML, as well as for other leukemic diseases.

Disclosures:

No relevant conflicts of interest to declare.