Sunday, October 17, 2010

Between epigenomic extremes

This post continues yesterday's discussion of epigenomic cancer.

There seem to be only two tumors in humans that can be conceptualized as pure epigenomic tumors: malignant rhabdoid tumors and germ cell tumors. These two tumors occupy opposite extremes of epigenomic alteration. In rhabdoid tumors, something happens that wrecks epigenomic control (bi-allelic INI1 loss), and this results in a tumor that has no specifiable developmental lineage. In germ cell tumors, the epigenome "reset" button is pressed, and the resulting germ cell tumors either have a globally "erased" epigenome, as in the case of true germinomas (e.g., seminomas in males), or they take any of the differentiation paths open to them (e.g., embryonal carcinomas, teratocarcinomas, choriocarcinomas, etc.).

Between the malignant rhabdoid tumors and the germ cell tumors are all the remaining tumors of humans (several thousand kinds). These tumors tend to have varying amounts of epigenomic and genomic alterations. We know this to be true because we see both types of changes in almost every malignant tumor. We see the evidence of genetic changes when we look at the many chromosomal anomalies found in malignant cells. We see the epigenomic changes when we see cytologic atypia characterized by light and dark areas of the nuclei (corresponding to alterations in chromosomal proteins), variations of chromatin distribution on the nuclear borders, abnormally shaped and sized nucleoli, etc.

Of course, there is an interplay between epigenome and genome in cancers. A good example is seen in acute promyelocytic leukemia.

In acute promyelocytic leukemia, a gene translocation produces the PML/RAR(alpha) fusion protein.[1] Normally, promyelocytes differentiate to become non-dividing myelocytes (neutrophils). Neutrophils are the major circulating nucelated cell and play a crucial role in inflammation and the body's defenses against infections. This fusion protein causes the promyelocyte to divide, producing more promyelocytes and fewer neutrophils. Eventually, the population of clonal promyelocytes arising from the neoplastic progenitor cell will attain a sufficiently large number to be recognized clinically as a promyelocytic leukemia.

Acute promyelocytic leukemia is one of the few cancers that can achieve clinical remission without treatment with cytotoxic agents. Remission is achieved with all-trans retinoic acid, which somehow causes the neoplastic promyelocytes to differentiate and become non-dividing mature myelocytes.[2]

The mechanism by which the neoplastic fusion protein, PML/RAR(alpha), induces a neoplastic phenotype and the mechanism whereby all-trans retinoic acid reverses the neoplastic phenotype seems to be mediated through the epigenome. It is hypothesized that PML/RAR(alpha) modifies histone deacetylase complexes resulting in the inappropriate transcriptional repression of genes would normally inhibit promyelocyte proliferation. All-trans retinoic acid is though to reverse this effect.[1] If this turns out to be the case, promyelocytic leukemia would serve as an example of a genetic mutation (fusion gene) that employs epigenomic alterations to sustain a neoplastic phenotype.

In later posts, we'll discuss the pure (or nearly pure) genetic cancers.

  1. Nouzova M, Holtan N, Oshiro MM, Isett RB, Munoz-Rodriguez JL, List AF, et al. Epigenomic changes during leukemia cell differentiation: analysis of histone acetylation and cytosine methylation using CpG island microarrays. J Pharmacol Exp Ther 311:968-981, 2004.
  2. Flynn PJ, Miller WJ, Weisdorf DJ, Arthur DC, Brunning R, and Branda RF. Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations. Blood 62:1211-1217, 1983.

-© 2010 Jules J. Berman

key words: cancer, neoplasia, epigenome, epigenetics, cytogenetics, neoplasms, precancer, tumor biology, tumour biology, carcinogenesis, cancer development, epigenomics, acute promyelocytic leukaemia, differentiation