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218 Part IV: Molecular and Cellular Hematology Chapter 16: Cell-Cycle Regulation and Hematologic Disorders 219

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regulatory pathways are affected by p21 . In addition, a basal p21 – tumor-suppressor functions, some of which are mediated by signaling
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cdk2 axis determines quiescent and cycling cell states and thus controls to p53. On the other hand, it has been shown that p14 ARF is able to drive
population heterogeneity in both normal cells and tumors, which can tumor progression in a p53-independent fashion, especially in myc-
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make anticancer treatment selectivity challenging. The molecule has driven lymphomas. 140
a p53 binding site in its promoter, and an increase in p53 levels results
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in transcriptional activation of p21 , slowing cell-cycle progression.
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In addition to this p53-dependent pathway, p21 is also regulated in PHARMACOLOGIC INHIBITION OF
a p53-independent manner. For example, histone deacetylase inhibitors
null
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(HDACIs) are able to induce p21 expression in p53 leukemia cells CYCLIN-DEPENDENT KINASES
through an alternative nuclear factor (NF)-κB–dependent mechanism, Perturbations of the cell cycle, for example, overexpression of cyclins or
which may limit the antileukemia activity of these agents. 121,122 Several underexpression of endogenous CDKIs, are nearly universal in human
binding partners of p21 , including Pim-1, have been identified. Pim-1 malignancies, and cdks, as critical regulators of cell-cycle progression
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cip1
associates with and phosphorylates p21 in vivo, which influences the and RNA transcription, represent attractive targets for anticancer drug
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subcellular localization of p21 . p21 is phosphorylated by Pim-1 development, as their inhibition can lead to both cell-cycle arrest and
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at two distinct sites, Thr145 and Ser146; phosphorylation on Thr apoptosis. 141,142 Additionally, pharmacologic inhibition of transcrip-
145
results in a nuclear localization of p21 and a disruption of the cell tional cdks, for example, cdk9, affects proteins with short half-lives,
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146
cycle, while phosphorylation on Ser leads to a cytoplasmic localization for example, the antiapoptotic proteins Mcl-1 and XIAP (X-linked
of p21 , suggesting that overexpression of Pim-1 in certain tumors inhibitor of apoptosis), cell-cycle regulators, p53, and NF-κB–respon-
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plays a key role in tumorigenesis. Like RB, expression and function of sive gene products. Hematologic malignancies may be particularly
125
142
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p21 is also affected by several different mechanisms, including muta- susceptible to cdk inhibition and apoptosis induction. A number of
tion and histone deacetylation (see “The Role of Histone Deacetylases pharmacologic CDKIs have been developed and subjected to various
in Cell-Cycle Regulation” below). Other members of the p21 family phases of preclinical and clinical testing in hematologic malignancies
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of CDKIs include p27 kip1 and p57 kip2 101,126 As a cdk inhibitor, p27 kip1 has (for a review, see Ref. 143). The selective cdk4/6 inhibitor palbociclib
.
tumor-suppressor activity. Besides cdks, p27 kip1 regulates additional cel- has been approved by the FDA as a potential treatment for hormone-
lular processes, including cell motility, some of which seem to mediate responsive metastatic breast cancer. In MCL, a disease characterized
the oncogenic activities of p27 kip1 . For example, the constellation of high by cyclin D overexpression, this agent has demonstrated encouraging
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p27 kip1 and low Myc expression is characteristic of chronic lymphocytic clinical activity. Whether selective or broad-spectrum inhibition is
144
leukemia (CLL) cells. These activities of p27 kip1 are regulated through the superior therapeutic strategy continues to be debated, and may be
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143
multiple phosphorylation sites. The multiple functions of p27 kip1 are tumor type-specific. The “pan-CDKI” flavopiridol (alvocidib), the first
dependent on a number of different conditions, and dictate whether CDKI to enter the clinic, has shown promising activity in patients with
the protein displays anti- or protumorigenic properties. High-level genetically high-risk chronic lymphocytic leukemia (CLL), particularly
128
expression of p27 kip1 leads to a cell-cycle block in G phase after treatment when administered by a pharmacologically derived “hybrid” sched-
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of cells with TGF-β. One major difference between p21 and p27 kip1 is ule, 145,146 but recent developmental efforts for this agent have focused on
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that the former binds predominantly to cdk2 whereas the latter binds AML, where it was recently granted “orphan drug” status. Flavopiri-
147
cdk4. dol induces apoptosis in primary leukemic blasts and recruits surviving
The cellular levels of a number of cell-cycle regulators, includ- leukemic cells into a proliferative state, thereby priming such cells for
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ing p21 and p27 kip1 , are regulated by ubiquitination and subsequent killing by S-phase-active cytotoxic agents such as cytarabine. 148,149 These
proteolysis. Polyubiquitinated proteins are degraded by the 26S protea- observations led to the design of “timed sequential therapy” regimens,
some complex. There are two major ubiquitination systems in the cell; for example, FLAM (flavopiridol, cytarabine, mitoxantrone), which
they are designated SCF and APC. 108,110 SCF is named for three of its core exhibited promising clinical activity in AML patients with nonfavorable
components, Skp, Cullin, and an F-box–containing protein. Important cytogenetics. Interestingly, both “bolus” and “hybrid” schedules of
150
examples of SCF substrates are Cln1, Sic1, Wee1, Cdc6/Cdc18, E2F, administration of flavopiridol produce comparably encouraging results
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.
cyclin D , cyclin E, p21 , p27 kip1 , and p57 kip2 129 in this setting. Other rational combinations involving pan-CDKIs
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A second group of CDKIs belongs to the inhibitor of the kinase such as flavopiridol or roscovitine involve those with proteasome inhib-
4 (INK4) family and includes p15 INK4B , p16 INK4A , p18 INK4C , and p19 IN itors (PIs), 152,153 HDACIs or BH3-mimetics. The first strategy has
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75
.
K4D 104,107,130,131 They all bind and inhibit the cyclin D –cdk4 and/or cyclin been explored in phase I trials in patients with recurrent or refractory
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D –cdk6 complex, which regulate cell-cycle progression via RB. 104,130 indolent B-cell neoplasms, 155,156 and a phase I trial of bortezomib and
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TGF-β is also a potent inducer of p15 INK4B 104 dexamethasone plus the pan-CDKI dinaciclib in patients with relapsed
, one of the mechanisms
by which the cytokine regulates the proliferation of hematopoietic cells myeloma is ongoing as of this writing (NCT01711528). Synergism in
(Chap. 16). p16 INK4A is probably the most important CDKI, because preclinical studies in leukemia between pan-CDKIs and HDACIs is
the gene is inactivated by several mechanisms (deletion, mutation, based predominantly on reciprocal effects on the cytoprotective NF-κB
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hypermethylation) in many different human cancers. Surprisingly, pathway and the endogenous cdk inhibitor p21 WAF1/CIP1 , besides Mcl-1/
p16 INK4A and p14 ARF are overexpressed in some cases of human hema- XIAP downregulation. Some of these phenomena have been recapitu-
154
133
tologic malignancies. This overexpression is probably a result of lated in patients with AML. 157
defects downstream of p16 INK4A , particularly caused by mutations in
the RB gene. In hematologic malignancies, the highest frequencies
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of p14 , p15 INK4B , or p16 INK4A inactivations are found in T-ALL, sec- CELL-CYCLE CHECKPOINTS
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ARF
ondary high-grade lymphomas, and mantle cell lymphoma (MCL). 136,137
The potency of p14 ARF and p16 INK4A in terms of tumorigenicity becomes The cell cycle progresses in an orderly fashion and is monitored by safety
obvious because the reexpression of both genes by either retroviral mechanisms known as cell-cycle checkpoints, which, upon activation,
transfection or demethylation of the promoter regions results in a com- function to halt cell division. When DNA damage occurs, distinct,
158
plete reversion of the malignant phenotype. 138,139 p14 ARF has multiple albeit overlapping and cooperating, checkpoint pathways are activated,
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