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238 Part IV: Molecular and Cellular Hematology Chapter 16: Cell-Cycle Regulation and Hematologic Disorders 239

ODC has been observed in many tumors and is linked to the Ras path- agents in hematologic malignancies. Transcriptional regulation
292
way. Reexpression of MTAP in ODC overexpressing cells decreases by methylation is mediated by a multiprotein complex consisting
278
279
ODC levels and inhibits tumor cell growth. In addition, high levels of a MeCP2, a methylcytosine-binding protein with a transcrip-
of 5′-deoxy-5′-(methylthio) adenosine (MTA) induce matrix metallo- tional repressor domain that binds the corepressor mSin3A, which
proteinase and growth factor gene expression in melanoma cells, lead- is itself one element of a multiprotein complex that includes HDAC1
ing to enhanced invasion and vasculogenic mimicry. In addition, MTA and HDAC2. 293,294 Therefore, reexpression of silenced genes can be
induced the secretion of β-fibroblast growth factor and the upregulation achieved by demethylating DNA or by destabilizing HDACs, and
of activator protein-1, demonstrating a tumor-supporting role of MTA, it could be demonstrated that both mechanisms are tightly linked.
which is increased in MTAP-deficient cells. 280 HDACIs and demethylating agents act synergistically to induce genes
139
The mechanisms by which the above-mentioned genes are inacti- silenced in cancer by hypermethylation. Another new mechanism
vated are rather different. Especially in permanent cell lines, p15 INK4B / of gene regulation and inactivation in vivo is degradation by microR-
p14 ARF /p16 INK4A and MTAP are homozygously deleted. One allele of NAs. This has also been shown for several members of the p16 INK4A /
MTAP is also deleted in AML lines, but not in primary AML samples. cdk4/cyclin D /RB pathway. 295
1
Mutations in p15 INK4B /p14 ARF /p16 INK4A genes are rare, and if present,
occur in exon 2. Hypermethylation of CpG islands in the promoter
areas of p15INK4B/p14 ARF /p16 INK4A are frequently found in hemato- THE ROLE OF HISTONE DEACETYLASES
logic malignancies. 281–283 The availability of demethylating agents such IN CELL–CYCLE REGULATION
as 5-azacytidine and 5-aza-2′-deoxycytidine (decitabine) makes this
phenomenon an interesting target for chemotherapy. 284,285 Decitabine HDACs catalyze the deacetylation of lysine residues in the histone
has been used to treat patients suffering from different hematologic N-terminal tails and are found in large multiprotein complexes
malignancies and was reported to have activity in advanced myelo- with transcriptional corepressors. Human HDACs are grouped into
dysplastic syndrome (MDS), accompanied by demethylation of the three classes based on their similarity to known yeast factors: class
p16 INK4A promoter. Azacytidine and decitabine are approved for I HDACs are similar to the yeast transcriptional repressor yRPD3;
285
the treatment of MDS 286–288 and also widely used for the treatment class II HDACs are similar to the yeast transcriptional repressor
of AML, particularly older patients considered unfit for cytotoxic yHDA1; and class III HDACs are similar to the yeast transcrip-
chemotherapy, particularly when blast counts are low. 289–291 However, tional repressor ySIR2 (Table 16–5; Fig. 16–3). 296,297 Eleven different
p16 INK4A and p15 INK4B are not the only targets of these demethylating HDACs have been identified so far. The physiologic counterparts of

TABLE 16–5. Different Types and Classes of Histone Deacetylases
Mechanism of Deacetylase
Enzyme Activity Tissue Expression Interacting Protein
Class I
HDAC1 Zn dependent Ubiquitous HDAC2, Sin3, CoREST, NuRD, RB/E2F1, p53, MYOD, NF-κB,
2+
YY1, DNMT1, DNMT3A, MBD2, SP1, SP3, BRCA1, MeCP2, ATM,
AML1-ETO, PML, PLZF, BCL6, AR, ER
HDAC2 Zn dependent Ubiquitous HDAC1, Sin3, CoREST, NuRD, RB, NF-κB, BRCA1, DNMT1,
2+
AML1-ETO, PML, PLZF, BCL6
HDAC3 Zn dependent Ubiquitous HDAC4, HDAC5, HDAC7, RB, NF-κB, STAT1, STAT3, GATA1,
2+
GATA2, NCoR/SMRT, AML1-ETO, PML, PLZF, PML-RARα, PLZF-
RARα, BCL6,
HDAC8 Zn dependent Ubiquitous SMC3, EST1B, Hsp70
2+
Class IIa
HDAC4 Zn dependent Tissue specific MEF2, HDAC3-NCoR, GATA1
2+
HDAC5 Zn dependent Tissue specific MEF2, HDAC3-NCoR, GATA1, GATA2
2+
HDAC7 Zn dependent Tissue specific MEF2, HDAC3-NCoR, ERα
2+
HDAC9 Zn dependent Tissue specific MEF2
2+
Class IIb
HDAC6 Zn dependent Tissue specific α-tubulin, Hsp90, HDAC11
2+
HDAC10 Zn dependent Tissue specific RB
2+
Class III
Sirt1–7 NAD dependent ? p53
+
Class IV
HDAC11 Zn dependent Tissue specific Interleukin 10, HDAC6
2+
HDAC, histone deacetylase; NAD, nicotinamide adenine dinucleotide; NF-κB, nuclear factor kappa B; RB, retinoblastoma.

Kaushansky_chapter 16_p0213-0246.indd 239 9/18/15 11:58 PM