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184 Part II Cellular Basis of Hematology

because cyclin E–CDK2 and cyclin D–CDK4 are inactivated by p21 APC/C that mediates degradation of cyclin B and securin. Inhibition
and p16, respectively, and RB remains capable of binding to and of CDC20 prolongs prometaphase until all chromosomes have
repressing the activating E2Fs, thereby decreasing levels of factors become correctly orientated on the metaphase plate. Unattached
required for DNA synthesis. In G 1, DNA damage is recognized by kinetochores recruit MCC through BUB1, leading to active MCCs.
ataxia-telangiectasia mutated (ATM) kinase, which in turn phos- Only when kinetochores have become correctly attached to the
phorylates histone variant H2AX to recruit repair factors and CHEK2 mitotic spindle is the MCC deactivated, which in turn activates APC/
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kinase. CHEK2-mediated phosphorylation activates p53 and C CDC20 and allows for mitosis progression.
inactivates CDC25A, which is required for the activation of cyclin
E–CDK2 complexes. The p53 target genes p21 and BTG2 further
promote cell cycle arrest at the G 1/S transition through inhibition of SPECIAL HEMATOLOGY CELL CYCLE FEATURES
cyclin E–CDK2 and activation of RB. If the DNA damage or stress
signals are repaired, cells can exit the G 1/S checkpoint and reenter Hematopoietic Stem Cells
the cell cycle.
Hematopoietic stem cells (HSCs) are characterized by their ability to
execute multiple cell fate choices, including self-renewal, quiescence,
S-Phase Checkpoint and differentiation into the many different mature blood cell types.
The stem cell niche forms the essential microenvironment for HSCs,
Under conditions that put DNA replication at risk, such as DNA and the primary HSC niche in adult organisms is located in the bone
damage or nucleotide depletion, the S-phase checkpoint gets acti- marrow. Stem cells are quiescent until prompted to proliferate by
vated. Ataxia telangiectasia and Rad3-related protein (ATR) is the external stimuli. Stem cell quiescence is achieved largely through the
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main kinase that senses DNA damage during S phase, and it phos- CDK inhibitors p21, p27, and p57. The pool of HSCs contains
phorylates CHEK1 kinase, which in turn activates p53. Similar to subsets that differ in self-renewal potential and cell division frequency.
the G 1 /S checkpoint, inhibition of cyclin E–CDK2 is central to the So-called short-term HSCs rapidly enter the cell cycle upon mitogen
S-phase checkpoint. The inhibition of CDK2 activity blocks loading stimulation, whereas long-term HSCs exit quiescence later. A recent
of CDC45 onto replication origins and prevents the initiation of new study showed that this difference is achieved at least in part through
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origin firing. In addition to inhibiting cyclin E–CDK2, p21 directly varying CDK6 levels in the HSC subsets. The absence of CDK6 in
interacts with PCNA to stop DNA replication. If the damage is long-term compared with short-term HSCs results in a delay in
repaired, cells continue DNA replication and cell cycle progression. quiescence exit, and the cumulative effect of this delay limits prolif-
eration of these cells and ultimately preserves long-term integrity of
the HSC pool.
G 2 /M Checkpoint

The G 2 /M checkpoint prevents cells from initiating mitosis when Endoreplication
DNA damage occurs during G 2 , or when cells progress into G 2
with some unrepaired damage inflicted during previous S or G 1 A special type of cell cycle progression is featured in the differentia-
phases. The G 2 /M checkpoint also involves DNA damage recognition tion of cells that have high metabolic profiles required for synthesis
by ATM and ATR kinases and subsequent p53 activation through of specific proteins, such as plasma proteins produced by hepatocytes,
CHEK1 and CHEK2 kinases, and it ultimately requires activa- or for the production of platelets by megakaryocytes (MKs). Throm-
tion of the p21 CDK inhibitor. If p21 is missing, both G 1 /S and bopoietin (TPO) is the major regulator that directs the growth and
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G 2 /M checkpoints are abolished. In addition to p21, p53 induces development of MKs from HSCs. TPO binds to the MK-specific
GADD45A and 14-3-3 (SFN), which contribute to G 2 /M cell receptor MPL, leading to MPL dimerization and activation of JAK2
cycle arrest. 14-3-3 removes essential mitotic regulators from the (Janus kinase 2). Initially, this signaling leads to endoreplication and
nucleus and thereby promotes G 2 /M arrest. Moreover, inhibition accumulation of DNA content of up to well over 128N before pro-
of cyclin-CDK activity through p21 induces DREAM and RB-E2F ceeding to final maturation and proplatelet formation. Endoreplica-
complexes, which in turn repress the transcription of the cell cycle tion requires impaired cyclin B–CDK1 kinase activity, which is
machinery. 12 achieved through upregulation of the CDK inhibitor p21 and induc-
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tion of the APC/C subunit CDH1 after S-phase completion. MK
endoreplication also requires the prevention of active RhoA through
Senescence downregulation of ECT2. During S phase, cyclin E–CDK2 inacti-
vates CDH1 to allow for proper DNA replication. As a result of the
If damage is not repaired timely, cells will enter a senescent state in following CDK1 inhibition, mitosis is completely bypassed after
which they remain viable but not capable of reentering the cell cycle. DNA replication. Inhibition of CDK1 and RhoA and activation
Telomere shortening, which signals cell aging, also is recognized as a of ACP/C CDH1 promote bypass of mitosis and entry into the next G 1
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type of DNA damage and can trigger senescence. RB is key in phase.
establishing the senescent state, which is activated downstream of p53
and the CDK inhibitors p16 and p21. During senescence, cells have
committed to proliferation and presumably have passed the restric- REFERENCES
tion point. In contrast to quiescence, senescent cells are unable to
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BUB1. To complete mitosis, the cell strictly requires the activity of 5. Coleman ML, Marshall CJ, Olson MF: RAS and RHO GTPases in
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