ASH News Daily 2012 - Saturday, December 8, 2012 - (Page A-4)

Page A–4 ® PEDIATRICS Seeing Advancements in Pediatric Leukemias in 3-D BY MICHAEL R. BISHOP, MD E very time a patient asks me why he or she should participate in one of my clinical trials, or for that matter any clinical trial, I share with him or her the tremendous success of clinical research in pediatric leukemias, particularly in acute lymphocytic leukemia (ALL). I remember older attending physicians sharing with me that there was a time when one quickly walked by the rooms of patients with acute leukemia while on rounds, as there was nothing that could be done except to keep them comfortable. Up until recently, it made me think of how we view patients with metastatic pancreatic cancer. Now, acute leukemia is one of the most curable malignancies in children, which is a result of careful and consistent dedication to clinical trials by physicians caring for these patients. However, there are, unfortunately, children for whom cure is elusive, and current research focuses on how to improve these outcomes through the translation of biologic discoveries into clinical protocols. These discoveries and transla- tional research efforts will be presented today “in 3-D” at 7:30 a.m. in Room A101, Level 1, Building A of the Georgia World Congress Center in the Education Program session, “Dynamic Discoveries and Directions in Pediatric Leukemias,” which will be chaired by Elizabeth Raetz, MD, from New York Univer- Epigenetics «« From Page A-2 expressed in multipotent HSCs, such as Runx1, Gata3, and others, were indeed hypomethylated; genes that are expressed in committed progenitors, on the other hand, were hypermethylated. When Dnmt3a is delivered exogenously in these null cells, methylation and cell differentiation are partially restored. Dr. Goodell will build on this work and show the data from double Dnmt3a and 3b knockout mice. She will then bridge normal and malignant hematopoiesis by discussing malignant development from the Dnmt3a knockout mice in the context of oncogenes. Dr. Goodell is also the William Dameshek Prize winner this year. Hypomethylation is only half of the story. Hypermethylation in the “wrong” set of genes (e.g., tumor suppressors) can lead to cancer. The ten-eleven translocation 2 (TET2) gene resides on chromosome 4q, and sity Medical Center. In planning this session, Dr. Raetz shared that she and her session presenters, Martin Schrappe, MD, of University Medical Center Schleswig-Holstein, Kiel, Germany, and Renier J. Brentjens, MD, PhD, of Memorial Sloan-Kettering Cancer Center, “felt this topic to be exciting, timely, and of considerable interest and relevance to both the pediatric and adult ALL communities.” Dr. Schrappe, who serves as chairman of the International BFM Study Group (iBFM), will discuss the clinical utility of monitoring minimal residual disease (MRD) in childhood ALL, as MRD response is now a key determinant of treatment assignment on many clinical protocols. He will focus on the different methodologies to monitor MRD, emphasizing the need for reliability and accuracy in MRD detection, as well as discuss the prospect of using MRD response as an endpoint for clinical interventions. Dr. Brentjens, who specializes in the treatment of both acute and chronic leukemias, will discuss the “state of the art” in cellular therapies for leukemia, focusing on adoptive therapy with T cells genetically modified to express tumor specific chimeric antigen receptors (CARs), particularly in regard to targeting CD19, which is expressed in B-cell ALL. Specifically, he will provide an overview of this emerging technology and discuss some early clinical trials utilizing CARs and the chal- TET2 oxidizes 5-methylcytosine (5-mC) on DNA to 5-hydroxymethylcytosine (5-hmC), resulting in natural demethylation. Dr. Olivier A. Bernard, PhD, Institut Gustave-Roussy, in Villejuif, France, who will follow Lucy A. Godley, MD, PhD, will further show the contribution of TET2 mutations in myeloid disorders, which leads to maintenance of methylation, starts at the stem cell level. He and his collaborators have shown that these mutations are present in a sizeable percentage (~15%) of myelodysplastic syndromes (MDS) and myeloproliferative diseases (MPD). What is interesting is that the TET2 mutations alone are identified in MDS and AML, but TET2 mutantions can precede the JAK2 mutations in MPD. But wait – TET2 mutations do not just lead to myeloid, but also to lymphoid malignancies. In the cohort of subjects with T-cell lymphoma that lenges in the interpretation of the results of these trials, emphasizing the need to harmonize clinical protocols among investigators. Finally, Dr. Raetz will discuss the disparity in the outcomes that exist in treating children with relapsed ALL, in contrast to the steady improvements that have been observed in newly diagnosed disease. She will note that outcomes for relapsed ALL have largely remained static in recent years and highlight how this has prompted interest in identifying and investigating new agents to study in this patient population. Dr. Raetz will also discuss the potential for using early measures of disease response to prioritize new therapies and to allocate treatment. If one included MRD Detection to Dynamic Discoveries and Directions, the session could almost be considered to be presented in 4-D. For those who miss the first session or want to come back for a second viewing, the session will be repeated on Monday at 7:00 a.m. in Room A103, Level 1, Building A. Unfortunately you will have to provide your own 3-D glasses. Dr. Bishop indicated no relevant conflicts of interest. ASH NEWS DAILY Saturday, December 8, 2012 Drs. Jennifer Davila and Julie Jaffray listen and take notes while Nancy Heddle, MSc, FCSMLS(D), discusses “Defining the Hypothesis/Research Question-Clinical Research” during Trainee Day on Friday afternoon. Phenotype Normal elderly individuals with skewed clonal hematopoiesis CMML AML Mutations Detected TET2 (in granulocytes only) TET2 TET2 or IDH he studied, DNMT3a and TET2 mutations were frequently observed together. Dr. Godley’s work at the University of Chicago has focused on how covalent cytosine modifications regulate hematopoiesis. Her laboratory has employed two techniques that distinguish between 5-mC and 5-hmC: mass spectrometry, which detects the total amount of each DNA base in a sample; and 5-hmC-affinity-Seq, which relies on chemical conjugation to isolate DNA loci enriched in 5-hmC. With these tools in hand, the Godley laboratory has studied the dynamics of 5-hmC alterations in normal hematopoiesis. She said, “The dramatic changes seen in 5-hmC content across hematopoietic cell differentiation emphasize how important it is for scientists to use techniques that can distinguish among the covalent cytosine modifications.” The altered balance of covalent cytosine modifications have been observed by Dr. Godley’s group in collaboration with several other labs, resulting in the phenotypes and mutations that are listed in the table above. Even if Dnmt3a knockout leads to hypomethylation, or TET2/IDH mutations leads to hypermethylation, there must be a way to stay young but somewhat in control. This special forum may just give us those clues. So while this is offered again on Sunday as a ticketed session (11:15 a.m., Omni Hotel at CNN Center), don’t miss out! Dr. Hsieh indicated no relevant conflicts of interest.

Table of Contents for the Digital Edition of ASH News Daily 2012 - Saturday, December 8, 2012

ASH News Daily 2012 - Saturday, December 8, 2012

https://www.nxtbookmedia.com