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CV#840A. Submitted to ASH 2001 Ann. Meet., 12/7-11, Orlando, FL.
HEMATOLOGIC
EPIGENETICS, GENOMICS, PROTEOMICS, & 1-CARBON METABOLISM 2002: SILENCING
ìBADî AND ACTIVATING ìGOODî DNA, mRNA TRANSCRIPTS, AND THEIR PROTEINS,
BY SELECTIVE TARGETED CHROMATIN METHYLATION AND DEMETHYLATION. Victor
D. Herbert, MD, JD, MACP. Mount Sinai-NYU Health
System & Bronx V.A. Medical Center, Bronx, NY, 10468 United States.
Ever
since Borek et al reported (1954)
that when bacteria auxotrophic for methionine are deprived of methionine,
their resultant less methylated RNA is under ìrelaxed controlî, i.e. is
synthesized more rapidly, he, we, and many others have been gathering evidence
that such ìrelaxed controlî also occurs in humans. Reviewing 3 decades of
such evidence in our 1983 paper ìThe Inhibition of Some Cancers and the
Promotion of Others by Folic Acid, Vitamin B12,
and Their Antagonistsî (Herbert V. In: Nutritional
Factors in the Induction and Maintenance of Malignancy [Butterworth CE Jr,
Hutchinson ML, Eds.]. New York: Academic Press, 1983:273-287), including
evidence that sickle cell disease could be ìtreatedî by producing folate
deficiency, which activated a sharp rise in fetal hemoglobin and fall in sickle
hemoglobin, we wrote, ìI should like to suggest the hypothesis that deficiency
of folate or vitamin B12, or any other cause of failure to methylate
DNA and/or RNA, can activate malignancy by hypomethylation of oncogenes, and
that methylating oncogenes can inhibit malignancy by making them dormant.... Perhaps
some of the second cancers that develop after successful antimetabolic
chemotherapy are due to the same chemotherapy that directly destroys an active
cancer, demethylating an oncogene of a dormant cancer.î With mapping of the
genome, it has become clear that any DNA, RNA, or proteome allele, normal or
variant, can be silenced by methylation or activated by demethylation
(due to methyl deficiency or demethylating agents such as 5-azacytidine).
As reviewed at the NIH August 6-8, 2001, Trans HHS Workshop, ìDiet,
DNA Methylation Processes, and Healthî (In press, J Nutr,
2002 ) it is now clear that the repression of transcription by DNA
methylation can occur through transcriptional repressive protein complexes (to
which one can make inactivating antibodies) such as Dnmts (DNA
methyltransferases) and HDACs (histone deacetylases). Hypermethylation is a
double-edged sword: suppressing oncogenes and/or their product RNAs and/or
proteins, and thereby suppressing cancer; and, conversely, suppressing the tumor
suppressor genes, RNAs, and proteins which suppress angiogenesis and metastasis,
and the DNA repair genes in malignant cells, thereby enhancing cancer growth and
spread. Now that (A Wolffe, F Urnov, others [Trans HHS Workshop, vide supra]), one can selectively epigenetically silence by targeted
methylation, with tailored zinc finger ìbulletsî, of
its unique nucleotide sequences (single nucleotide polymorphisms) (SNPs,
travelling in groups [haplotypes]) any gene variant chromatin target we wish,
without methylating other genes, we are on the road, as we uncover their target
nucleotide sequences (their promoter regions), to prevention and cure of all
hematologic disorders associated with inherited or acquired gene variant
chromatin that can be silenced by targeted methylation, including the
myeloproliferative disorders, hemoglobinopathies, thalassemias, sideroblastic
anemias, red cell enzyme defects, iron overload disorders, coagulation defects,
and autoimmune disorders. Before clinical stigmata appear, one can isolate from
the peripheral blood, by using microarray plates and other high-throughput
genetic analysis instrumentation (C M Henry. Pharmacogenomics. Chem & Eng
News, 2001; 79 (33): 37-42), not only these hematologic SNP targets but also
non-hematologic targets, since even clinically undetectable early breast and
prostate cancer constantly shed a few cells into the circulating blood (Trans
HHS Workshop, vide
supra).
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