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CHAPTER 16 given an empirical definition: When the occurrence of event B is depen-
dent on the completion of prior event A, the dependence is a result of a
CELL-CYCLE REGULATION checkpoint if a loss-of-function mutation can be found that relieves the
1
dependence. Three major cell-cycle checkpoints have been discovered:
AND HEMATOLOGIC the DNA damage checkpoint, the replication checkpoint, and the spin-
dle-pole body duplication checkpoint. The functional consequence of
2–4
failure to “satisfy” the requirements of a cell-cycle checkpoint is usually
DISORDERS 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 miss-
ing one or more checkpoints, which facilitates a greater rate of genomic
Yun Dai, Prithviraj Bose, and Steven Grant evolution. 5
A disturbance of cell-cycle regulation is an important pathway
in the development of many hematologic malignancies as a result of
SUMMARY 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
Complex feedback pathways regulate the passage of cells through the G , S, mutation (gain-of-function or loss-of-function mutations). Progress in
1
G , and M phases of the growth cycle. Two key checkpoints control the com- the understanding of the regulation of gene expression put emphasis
2
mitment of cells to replicate DNA synthesis and to mitosis. Many oncogenes on another mechanism of gene inactivation, called epigenetic regulation
and defective tumor-suppressor genes promote malignant change by stimu- (Chap. 10). This term summarizes several molecular modifications,
lating cell-cycle entry, or disrupting the checkpoint response to DNA damage. including histone deacetylation, CpG-island hypermethylation, ubiq-
Advances in the understanding of genetic and epigenetic mechanisms of gene uitination, and phosphorylation, etc.
regulation provide the basis for novel therapeutic approaches. This chapter
presents the pathways and the genetic and epigenetic alterations that regu-
late cell replication, and highlights the various oncogenes and tumor-suppressor CYCLINS AND CYCLIN-DEPENDENT
genes that are involved in hematologic malignancies. KINASES
Table 16–1 lists Cdks, associated partners, and their functions.
Mitosis is the final step of a defined program—the cell cycle—that can Early experiments on the control of mitosis in human cells pro-
be separated into four phases: the G , S, G , and M phases (Fig. 16–1). vided evidence for the existence of factors called M-phase and S-phase
1
2
6
A number of surveillance systems (checkpoints) control the cell cycle promoting factors. The key element of S-phase promoting factor was
and interrupt its progression when DNA damage occurs or when cells thought to be cell division cycle (cdc) 2. Experiments performed in Xen-
7
have failed to complete a necessary event. These checkpoints have been opus eggs showed that cdc2 is an M-phase–specific histone H1 kinase,
1
but is just one subunit of a regulatory complex. A second component
is cyclin B, which is synthesized in interphase and degraded in mid-
mitosis. More than 10 members of the mammalian cyclin family have
Acronyms and Abbreviations: ALL, acute lymphoid leukemia; AML, acute been identified. Most of these cyclins interact with a group of cdc2-
8,9
myelogenous leukemia; APC, anaphase-promoting complex; APL, acute pro- related kinases called cyclin-dependent kinases (cdks), while others are
10
myelocytic leukemia; ATM, ataxia-telangiectasia mutated; ATR, ATM and Rad3 involved in alternate splicing processes. Phosphorylation of tyrosine
related; cdc, cell division cycle; cdk, cyclin-dependent kinase; CDKI, cyclin- 15 is the key event in regulating human cdc2 activity. Threonine 14 also
dependent kinase inhibitor; Chk, checkpoint kinase; CLL, chronic lympho- is phosphorylated in G phase. Dephosphorylation at both phosphory-
2
cytic leukemia; CML, chronic myelogenous leukemia; CTD, carboxy-terminal lation sites is required for mitotic initiation. Cdc2 interacts with cyclin B
in mitosis, whereas the cdc2/cyclin A complex is formed before mitosis
domain; DDR, DNA damage response; DSIF, DRB-sensitivity–inducing factor; and is required for progression through late G phase. Thus, cyclins
11
2
ER, endoplasmic reticulum; FLAM, flavopiridol, cytarabine, mitoxantrone; A and B are also called the mitotic cyclins, because they are upregu-
GADD, growth arrest and DNA damage; HAT, histone acetyltransferase; HDAC, lated in late G or G /M phase and undergo proteolysis in M phase.
2
2
histone deacetylase; HDACI, histone deacetylase inhibitor; HR, homologous The exit from mitosis is characterized by the abrupt ubiquitination and
recombination; Id1, inhibitor of DNA-binding 1; INK4, inhibitor of kinase 4; subsequent degradation of cyclin B. Cells with a defective cyclin B deg-
JAK, Janus-associated kinase; MAPK, mitogen-activated protein kinase; MCL, radation mechanism or without mitotic cyclin B easily become aneu-
mantle cell lymphoma; MDM2, murine double minute protein 2; MLL, mixed- ploid. There is evidence that cyclin A acts at the G /M transition and
2
lineage leukemia; MTA, 5′-deoxy-5′-(methylthio)adenosine; MTAP, methylth- binds cdk2 in S phase. Cyclin A is mandatory for the downregulation
12
ioadenosine phosphorylase; NELF, negative elongation factor; N-TEF, negative of anaphase-promoting complex (APC). Overexpression of cyclin A
13
transcription elongation factor; ODC, ornithine decarboxylase; PDGF, platelet in G phase leads to an accelerated entry into S phase. Because cdc2 is
1
derived growth factor; PI3K, phosphatidylinositol 3′-kinase; PLZF, promyelo- able to interact with mitotic and G cyclins, it is likely that one protein
1
kinase potentially can fulfill several different functions in the cell cycle
cytic leukemia Kruppel-like zinc finger; PML, promyelocytic leukemia; P-TEFb, at various checkpoints. Notably, there is increasing evidence that cdc2
positive transcription elongation factor; RARα, retinoic acid receptor α; RB, is directly involved in regulating the DNA damage response (DDR),
retinoblastoma gene; rPTK, receptor protein-tyrosine kinase; STAT, signal including DNA damage checkpoint activation and DNA repair (partic-
transducer and activator of transcription; TGF-β, transforming growth fac- ularly homologous recombination [HR]). There are several cdc2-re-
14
tor-β; TKI, tyrosine kinase inhibitor; UPR, unfolded protein response. lated protein kinases in humans that interact with the corresponding
cyclins. Originally, three cdc2-related proteins were isolated, which
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