By Michael McDevitt, MD, PhD

2008-12-08

Epigenetic marks represent DNA modifications of genomic DNA or associated proteins, other than the DNA sequence itself, that are heritable through cell division. These include: DNA methylation, a covalent modification of cytosine; histone modifications affecting the nucleosomes around which the DNA is coiled; and alterations in nucleosomal packing or higher-order folding of chromatin. Acquired epigenetic changes are now recognized to be common in human malignancy, and hematologic research has provided many of the insights we currently appreciate. This week of December in 1991, Steve Baylin’s group published in Blood the identification of malignant cells isolated from either peripheral blood or bone marrow that contained calcitonin promoter methylation that correlated with CML disease progression. We still have much to learn, but certainly this meeting has provided important and interesting steps forward, with great promise for the future. The role of epigenetic regulation of hemoglobin switching was highlighted in Saturday’s ASH News Daily. The demethylating agents 5-Aza-2’deoxycytidine (decitabine, DAC) and 5-azacytidine (AZA) at low doses induce hematologic and cytogenetic remission in a subset of patients with myelodysplastic syndrome (MDS), and Dr. David Steensma’s article on page A-6 in today’s issue discusses progress with these and other epigenetic and non-epigenetic therapies as applied to MDS. The promising applications of demethylating agents to patients with the myeloproliferative disorders CMML and CML have been presented previously at ASH and continue to be studied. In Sunday’s education session on myeloproliferative disorders, Dr. Alessandro Rambaldi, from the Unit of Hematology, Ospedali Riuniti Bergamo, in Italy, reviewed the biology (including calcitonin gene methylation) and current therapy for myelofibrosis during his talk titled “From Palliation to Epigenetic Therapy in Myelofibrosis.” Methylation inhibitors, histone deacetylase inhibitors, and many other agents were discussed. Chronic idiopathic myelofibrosis typically demonstrates a progressive clinical course with a usually poor lethal prognosis, and new therapies are very much needed.

Identification of the mechanisms by which chromatin-modifying agents alter normal and malignant hematopoiesis will be necessary to fully exploit current clinical successes and early observations. Dr. Ari Melnick, of Weill Cornell Medical College, gave us insight into the complexity of this task during the Saturday and Sunday session titled Genomics and Epigenomics in the Myeloid Malignancies. His presentation, “Genome-Wide Epigenetics in Myeloid Leukemias,” provided insights into oncogenic pathways, genomic instability, and leukemia translocation fusion protein modifications with subsequent effects on gene dysregulation. His group’s work suggests that the identification of DNA methylation profiles associated with specific clinical groups may provide important diagnostic and prognostic information and therapeutic targets for acute myeloid leukemias.

There is growing evidence for significant epigenetic regulation of hematopoietic stem cell (HSC) function and perhaps dysfunction as hematopoietic stem cells age. In a session on hematology and aging, Dr. Margaret Goodell, of Baylor College of Medicine in Houston, reviewed fascinating insights into this topic. Results from her laboratory and others indicate HSCs are subject to extensive epigenetic changes over time. Her detailed investigations of aging murine stem cells have major implications for our understanding of age-related hematologic malignancy predispositions, pathogenesis of bone marrow failure conditions, and hematologic reconstitution therapies of the future. Read more about her presentation to learn more.

Application of chromatin-modifying/epigenetic drugs to normal HSC cultures with cytokines with a goal of preservation of marrow-repopulating activity and HSC self-renewal, but expanding potential therapeutic grafts to allow more effective transplantation, were investigated in several of the poster presentations at the meeting. The breadth of the epigenetic investigations presented at this year’s ASH meeting might be interpreted as a veritable epigenetics epidemic.

Dr. McDevitt indicated no relevant conflicts of interest.

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