Loss of EGR-1 Accelerates BCR-ABL-Driven Leukemogenesis

Abstract 1671

Chronic Myelogenous Leukemia (CML) is a disease resulting from the neoplastic transformation of hematopoietic stem cells (HSC) by the translocated tyrosine kinase BCR/ABL. The BCR-ABL protein product 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. The early growth response (Egr)-1 gene, a member of the Egr family of genes encoding for zinc-finger transcription factors, has been shown to be an early response gene, to mediate cellular responses to growth factors and to be a stress response gene. Both growth factor stimulation and stress in most cells causes rapid induction of Egr-1 within minutes that leads to the activation of downstream growth pathways in normal cells. Egr-1 regulates the expression of multiple genes, either directly or indirectly, that impact on cell cycle arrest, survival and/or apoptosis, which can interface with BCR-ABL signaling. Included among these genes are p53, TGFbeta, PTEN, gadd45a, gadd45b, Foxo3a, p21, FasL, and Trail.

There is a large body of evidence consistent with Egr-1 behaving as a tumor suppressor in hematopoietic cells, both in vivo & in vitro, in both humans & mice. This laboratory has shown that Egr-1 abrogates the block in M1 terminal differentiation imparted by either oncogenic c-Myc or E2F-1, suppressing their leukemia promoting function in nude mice. Since Egr-1 can be a tumor suppressor and its down-stream effectors cross-talk with BCR-ABL signaling it was asked if Egr-1 can act as a suppressor of BCR-ABL driven leukemogenesis. To assess the effect of Egr-1 on BCR-ABL driven leukemia, syngeneic wild type lethally irradiated mice were reconstituted with wild type or Egr-1 null myeloid progenitors transduced with a 210-kD BCR-ABL-expressing MSCV-retrovirus. It was observed that loss of Egr-1 accelerated the development of BCR-ABL driven leukemia in recipient mice. In vitro proliferation assays have shown enhanced proliferation capacity for BCR-ABL transduced Egr-1 null myeloid progenitors compared to wild type counterparts. In addition, flow cytometric analysis of Egr-1 null myeloid progenitors from bone marrow (BM) has shown a slightly smaller stem cell (Lineage- Sca+ and c-Kit+ [LSK]) population as compared to wild type progenitors from BM. Therefore, the accelerated induction of BCR/ABL-mediated leukemia using Egr-1 null progenitors cannot be accounted for by increased numbers of stem cells. Taken together, these results indicate that Egr-1 functions as a suppressor of BCR-ABL driven CML. Further elucidating the role of Egr-1 in the murine model of BCR-ABL driven leukemia and analysis of Egr-1 expression in human CML peripheral blood and BM could result in novel targets for diagnosis and prognosis, as well as for targeted therapeutics.