HIGHLIGHTS OF THE 46TH ASH ANNUAL MEETING

PETER EMANUEL, M.D.

Dr. Emanuel is the Acting Director of the University of Alabama at Birmingham Comprehensive Cancer Center and was the Editor of ASH News Daily 2004.

In a rare occurrence, the 46th ASH Annual Meeting was held in the same location as the 45th ASH Annual Meeting. Did that equate to a re-hash of last year's material? Hardly. The invited speaker list read like a Who's Who, not just in hematology, but a Who's Who of the top scientists from a multitude of fields. Perhaps one of the notable speakers, Dr. Gary Gilliland, phrased it best when he commented that he dreamed he was speaking at the ASH meeting, only to have the dream turn to a nightmare when he realized he was immediately following Dr. Brian Druker's talk.

The Ham-Wasserman Lecture was presented by Dr. Doug Higgs from the Weatherall Institute of Molecular Medicine in Oxford. Dr. Higgs began his Ham-Wasserman Lecture with an overview of the thalassemia syndromes, portraying the free αglobin chains as the villain in β-thalassemia. He spoke of the current management and outlook for patients with thalassemia and their families. He also talked of approaches to potentially alter the chain imbalance in thalassemia. The epigenetic program in thalassemia is now being defined, and mutations in the ATRX gene affect patterns of DNA methylation. The ATRX gene is present on the X chromosome and affects αglobin expression. It was identified through patients who develop the ATMDS syndrome, a combination of acquired a thalassemia and myelodysplasia.

Many of us regard Dr. Donald Metcalf, from The Walter and Eliza Hall Institute of Medical Research in Australia, as the father of cytokines. Thus, it was a real treat for ASH attendees to hear him deliver the E. Donnall Thomas Lecture. And ASH News Daily featured a great picture of Donnall and Dottie Thomas listening to Dr. Metcalf as he delivered a wonderful journey from the past to the present. He chronicled the early days of colony growth, cytokine identification and characterization, and the move of cytokines to the clinical setting. He also gave an update on more recent explorations utilizing expression-screening to discover the SOCS family of inducible intracellular inhibitors of cytokine signaling.

This year's Plenary Scientific Session was truly diverse and exciting. We heard of a second generation kinase inhibitor for CML, which appears to be effective in imatinib-resistant cases. We heard of ingeniously conceived new methods of genome-wide screening to identify genetic modifiers of thrombotic mechanisms. We learned of new pathogenetic mechanisms that have been identified involving the TERT gene in aplastic anemia and the NOTCH1 gene in T cell ALL. We also heard that specifically disrupting peptides is being explored as a therapeutic approach in lymphomas. Finally, many listeners were surprised by results showing hydroxyurea to be better than anagrelide in some essential thrombocythemia patients.

The ASH/ASCO Joint Symposium was entitled "Common Targets in Hematological and Non-Hematological Malignancies," was chaired by Dr. Stanley Schrier, 2004 President of ASH, and Dr. David Johnson, President of ASCO, and featured Dr. Charles Sawyers from UCLA, Dr. Scott Hiebert from Vanderbilt, and Dr. Daniel Tenen from Harvard. Dr. Sawyers focused on targeting cancers that are known to be kinase-dependent or "kinase-driven." Imatinib has given us a wonderful example that proves that kinase inhibitors can have significant activity in these "kinase-driven" malignancies. The questions, as so vividly explained by Dr. Sawyers, are: can these inhibitors work in other types of malignancies and just how many cancers have mutant kinases? Dr. Sawyers believes that the answer to the latter question likely will soon come from the cancer kinome sequencing effort. Dr. Hiebert explained how the RUNX family members are involved in AML, B cell ALL, gastric, and colon cancers. He further showed studies that detailed how RUNX1 cooperates with C/EBPα and ETS factors to activate NF1. Finally, Dr. Tenen talked about the role of C/EBPα in AML and lung cancer. He asserts that in most adult systems, transcription factors (not growth factors) direct differentiation, and that knockdown mechanisms, but not necessarily knockout mechanisms, of transcription factors may be important in cancer. He also gave a glimpse into the potential future of "transcription therapy."

The ASH Presidential Symposium continues to be one of the most entertaining scientific forums of the meeting. Attendees who traditionally skip out early and miss Tuesday's events are really cheating themselves out of some of the best science of the entire meeting. This year's Presidential Symposium held true to form with brilliant presentations from Dr. Michael Kastan from St. Jude Children's Research Hospital, Dr. Frederick Alt from the Children's Hospital at Harvard, and Dr. Alan D'Andrea from the Dana-Farber Cancer Institute. The title of the symposium was "Genomic Instability and DNA Repair in Hematology." Dr. Kastan spoke of DNA damage as the root of everything, given the paradox that DNA damage causes cancer but that DNA damage is also a mechanism employed to cure cancer and that DNA damage causes the toxicity of chemotherapy. He detailed the investigations characterizing ATM as a protein kinase that is extraordinarily rapidly, sensitively, and extensively phosphorylated. This characteristic might just make inhibitors to ATM therapeutic agents that may make tumors hypersensitive to radiation. Amongst the many topics covered by Dr. Alt, he spoke of how ΥH2AX functions as a scaffold for the assembly of multiple protein/DNA complexes. H2AX-deficient cells thus lack a suitable anchor and therefore aberrant DNA repair occurs, leading to translocations. The final story of the 46th ASH Annual Meeting was presented by Dr. D'Andrea and brilliantly showed listeners how Fanconi anemia (FA) has now been linked to breast cancer. ATR senses DNA damage and turns on the FA enzyme complex leading to monoubiquitination of the D2 protein. FANCD2 interacts with D1 and RAD51 with subsequent DNA repair. The FA D1 gene is identical to the BRCA2 breast cancer gene. Amazingly, breast cancer cells have many similarities to Fanconi anemia cells.

The Ham-Wasserman Lecture, E. Donnall Thomas Lecture, ASH-ASCO Joint Symposium, and Presidential Symposium are accessible online through the ASH Web site.

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