The proto-oncogene c-myc in hematopoietic development and leukemogenesis

Abstract

The proto-oncogene c-myc has been shown to play a pivotal role in cell cycle regulation, metabolism, apoptosis, dierentiation, cell adhesion, and tumorigenesis, and participates in regulating hematopoietic homeostasis. It is a transcription regulator that is part of an extensive network of interacting factors. Most probably, dierent biological responses are elicited by dierent overlapping subsets of c-Myc target genes, both induced and suppressed. Results obtained from studies employing mouse models are consistent with the need for at least one, and possibly two, mutations in addition to deregulated c-myc for malignant tumor formation. Repression of c-myc is required for terminal dierentiation of many cell types, including hematopoietic cells. It has been shown that deregulated expression of c-myc in both M1 myeloid leukemic cells and normal myeloid cells derived from murine bone marrow, not only blocked terminal dierentiation and its associated growth arrest, but also induced apoptosis, which is dependent on the Fas/CD95 pathway. There is evidence to suggest that the CD95/Fas death receptor pathway is an integral part of the apoptotic response associated with the end of the normal terminal myeloid dierentiation program, and that deregulated c-myc expression can activate this signaling pathway prematurely. The ability of egr-1 to promote terminal myeloid dierentiation when coexpressed with c-myc, and of c-fos to partially abrogate the block imparted by deregulated c-myc on myeloid dierentiation, make these two genes candidate tumor suppressors. Several dierent transcription factors have been implicated in the down-regulation of c-myc expression during dierentiation, including C/EBPa, CTCF, BLIMP-1, and RFX1. Alterations in the expression and/or function of these transcription factors, or of the c-Myc and Max interacting proteins, such as MM-1 and Mxi1, can in¯uence the neoplastic process. Understanding how c-Myc controls cellular phenotypes, including the leukemic phenotype, should provide novel tools for designing drugs to promote dierentiation and/ or apoptosis of leukemic cells.

Egr-1 abrogates the E2F-1 block in terminal myeloid differentiation and suppresses leukemia

“…Lesions in genes that control differentiation may lead to either anemia or leukemia (Hoffman et al, 2002). The autonomously proliferating M1 myeloblastic leukemia cell line is induced by interleukin-6 (IL-6) to undergo terminal macrophage differentiation with concomitant loss of leukemogenicity, providing an attractive model system to analyse the different regulators of terminal differentiation.…”

Distinctive gene expression pattern in VH3-21 utilizing B-cell chronic lymphocytic leukemia

“…The down-regulated MXI-1 protein is another transcriptional repressor that has been shown to interact with MAX and result in MYC activation. 39 The down-regulated cyclin-dependent kinase (CDK) inhibitor 1B (CDKN1B, p27, Kip1) and cyclin-dependent kinase inhibitor 2D (CDKN2D, p19, inhibits CDK4) are both proteins that bind to CDKs and prevents G1 progression. 40 The ING1 tumor suppressor interacts with p53, thereby promoting cell-cycle arrest and apoptosis, and has been reported to show decreased expression in both lung cancer and acute lymphoblastic leukemia (ALL).…”

Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

“…However, the deregulation of c-Myc has been observed in a wide range of human cancers, particularly leukemias and lymphomas, due to gene amplification, translocation, transactivation, or increased protein stability. Deregulated c-Myc increases genomic instability, blocks differentiation, and is able to induce lymphoid and myeloid neoplasia, making it an attractive target for cancer treatment (8)(9)(10).…”