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Complex feedback pathways regulate the passage of cells through the G1, S, G2, and M phases of the growth cycle. Two key checkpoints control the commitment of cells to replicate DNA synthesis and to mitosis. Many oncogenes and tumor-suppressor genes promote malignant change by stimulating cell-cycle entry, or disrupting the checkpoint response to DNA damage. Advances in the understanding of epigenetic gene expression regulation provide the basis for novel therapeutic approaches. This chapter presents the pathways as well as the genetic and epigenetic alterations that regulate cell replication and tabulates the various oncogenes and tumor-suppressor genes that are involved in hematologic malignancies.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: AML, acute myelogenous leukemia; APL, acute promyelocytic leukemia; cdk, cyclin-dependent kinase; CML, chronic myelogenous leukemia; HAT, histone acetylases; HDAC, histone deacetylase; HDACi, histone deacetylase inhibitor; INK4, inhibitor of kinase 4; MTAP, methylthioadenosine phosphorylase; PLZF, promyelocytic leukemia Kruppel-like zinc finger; RARα, retinoic acid receptor-α; rPTK, receptor protein-tyrosine kinase; TGF-β, transforming growth factor-β.

Cellular mitosis is the final step of a defined program—the cell cycle—that can be separated into four phases: the G1, S, G2, and M phases (Fig. 13–1). A number of surveillance systems (checkpoints) control the cell cycle and interrupt its progression when DNA damage occurs or when the cells have failed to complete a necessary event.1 These checkpoints have been given an empirical definition: When the occurrence of an event B is dependent on the completion of prior event A, the dependence is a result of a checkpoint if a loss-of-function mutation can be found that relieves the dependence.1 Three major cell-cycle checkpoints have been discovered: the DNA damage checkpoint, the spindle checkpoint, and the spindle-pole body duplication checkpoint.2–4 The functional consequence of failure to “satisfy” the requirements of a cell-cycle checkpoint is usually death by apoptosis. However, small numbers of genetically altered cells may survive. Cells with defective checkpoints have an advantage when selection favors multiple genetic changes. Cancer cells are often missing one or more checkpoints, which facilitates a greater rate of genomic evolution.5

Figure 13–1.

Cell-cycle regulation in mammalian cells.

A disturbance of cell-cycle regulation is an important pathway in the development of many hematologic malignancies as a result of mutations in tumor-suppressor genes or oncogenes. Until the end of the 20th century, it was believed that the only mechanism by which the “gatekeepers” of the cell cycle could be inactivated was deletion or mutation (gain-of-function or loss-of-function mutations). Progress in the understanding of the regulation of gene expression put emphasis on another mechanism of gene inactivation, called epigenetic regulation (see Chap. 10). This term summarizes several molecular modifications, including histone deacetylation, CpG-island hypermethylation, ubiquitination, and phosphorylation.

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