Chilhood Lukemia's - Steps Forward and Steps Back, But Progress Any Way You Measure It.

By Peter Emanuel, M.D.

Molecular Forensics: a powerful concoction of astute physician-scientists together with new mo- lecular diagnostics to predict when childhood development leukemic translocations are actually occurring. Two major sessions, a plenary abstract, and a multitude of other oral presentations and posters deal with pediatric leukemias. The Scientific Committee on Pediatric Hematology examines The Molecular Origin and Ontogeny of Childhood Leukemia. Chaired by Dr. Peter Newburger, the committee met on Saturday afternoon. An educational session on Pediatric ALL was presented Saturday afternoon and will be presented again today from 7:30 a.m. - 9:15 a.m. The Scientific Committee meeting was an exciting mix of topics by three brilliant scientists. Dr. Wiemels' investigations seek to define the crucial temporal and developmental windows, during which time genetic aberrations may be al- lowed to develop in susceptible stem cells. Utilizing this approach in examining pediatric ALL, Dr. Wiemels has been able to sort out the critical temporal window period for two recurring chromosomal translocation subtypes within ALL. In t(12;21) TEL-AML1, they have evidence that this is prenatal in origin because this type of translocation displays a molecular fingerprint of DNA damage and non- conservative repair processes, rather than a pattern of site-specific recombination, indicative of a trans- location occurring in an early proliferating progenitor cell. On the other hand, in t(1;19) E2A-PBX1, there is strong evidence for a postnatal origin, based on its presence on neonatal heel-prick Guthrie cards, as well as evidence of V(D)J recombinase-associated TdT activity in the translocation process. They also have evidence that children with leukemias harboring NRAS and KRAS mutations may link back to prenatal events and parental smoking histories. Thus, this detective work performed by Dr. Wiemels demonstrating evidence of RAS mutations "backtracking to birth" and the identification of specific temporal windows during which leukemias may develop, provides the tools necessary to fur- ther investigate the true causes of childhood leukemias.

The work of Dr. Crispino and others is investigating the relationship of GATA1 mutations with the development of Transient Myeloproliferative Disorder (TMD) or Acute Megakaryoblastic Leukemia (AMKL) in Down Syndrome children. The question was when during the evolution of DS myeloid leukemogenesis are the GATA1 mutations manifested? It appears that the GATA1 muta- tions are a fairly early event in this progression model and contribute to the development of both TMD and AMKL, rather than a more mid-event, in between TMD and AMKL as some would have predicted. Again, as with Dr. Wiemels' studies, knowledge of when these mutational events are occuring will likely lead to a better understanding of disease progression and also yield clues as to the other events preceding or following the GATA1 mutations.

Finally in this committee meeting, Dr. Copeland presented his series of studies of utilizing retroviral insertional mutagenesis to identify candidate cancer gene loci as well as novel cancer genes.

In the Educational Session on Pediatric Acute Lymphoblastic Leukemia, Dr. Carroll reviewed the current approaches to risk classification and proposed a system incorporating clinical parameters, genetic lesions in the blast cell, and early response parameters. He also provided a very lucid glimpse into the future of how the emerging technologies in genomics and proteomics might completely alter the classification landscape. Dr. Davies gave an overview of the ro le that genetic polymorphisms can play in drug metabolism. An illustrative example was that of TPMT deficiency, a key enzyme in 6-mercaptopurine metabolism. Individuals deficient in this enzyme demonstrate markedly increased toxicity. Drs. Downing and Willman both delivered high-tech, exciting lectures on the usefulness of gene expression profiling and how these investigations may quite soon allow us to better stratify patients in terms of outcome probabilities and risk profiles. Fi- nally, Dr. Reed gave a comprehensive overview of the multiple and intricately linked cell death pathways and how they may be eventually applicable to childhood ALL.