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INTRODUCTION

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SUMMARY

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 defective tumor-suppressor genes promote malignant change by stimulating cell-cycle entry, or disrupting the checkpoint response to DNA damage. Advances in the understanding of genetic and epigenetic mechanisms of gene regulation provide the basis for novel therapeutic approaches. This chapter presents the pathways and the genetic and epigenetic alterations that regulate cell replication, and highlights the various oncogenes and tumor-suppressor genes that are involved in hematologic malignancies.

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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. 16–1). A number of surveillance systems (checkpoints) control the cell cycle and interrupt its progression when DNA damage occurs or when cells have failed to complete a necessary event.1 These checkpoints have been given an empirical definition: When the occurrence of 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 replication checkpoint, and the spindle-pole body duplication checkpoint.2,3,4 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 often are missing one or more checkpoints, which facilitates a greater rate of genomic evolution.5

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Acronyms and Abbreviations:

ALL, acute lymphoid leukemia; AML, acute myelogenous leukemia; APC, anaphase-promoting complex; APL, acute promyelocytic leukemia; ATM, ataxia-telangiectasia mutated; ATR, ATM and Rad3 related; cdc, cell division cycle; cdk, cyclin-dependent kinase; CDKI, cyclin-dependent kinase inhibitor; Chk, checkpoint kinase; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CTD, carboxy-terminal domain; DDR, DNA damage response; DSIF, DRB-sensitivity–inducing factor; ER, endoplasmic reticulum; FLAM, flavopiridol, cytarabine, mitoxantrone; GADD, growth arrest and DNA damage; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDACI, histone deacetylase inhibitor; HR, homologous recombination; Id1, inhibitor of DNA-binding 1; INK4, inhibitor of kinase 4; JAK, Janus-associated kinase; MAPK, mitogen-activated protein kinase; MCL, mantle cell lymphoma; MDM2, murine double minute protein 2; MLL, mixed-lineage leukemia; MTA, 5′-deoxy-5′-(methylthio)adenosine; MTAP, methylthioadenosine phosphorylase; NELF, negative elongation factor; N-TEF, negative transcription elongation factor; ODC, ornithine decarboxylase; PDGF, platelet derived growth factor; PI3K, phosphatidylinositol 3′-kinase; PLZF, promyelocytic leukemia Kruppel-like zinc finger; PML, promyelocytic leukemia; P-TEFb, positive transcription elongation factor; RARα, retinoic acid receptor α; RB, retinoblastoma gene; rPTK, receptor protein-tyrosine kinase; STAT, signal transducer and activator of transcription; TGF-β, transforming growth factor-β; TKI, tyrosine kinase inhibitor; UPR, unfolded protein ...

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