Characterization of MLL Gene Rearrangement in Acute Leukemia

Chromosome 11q23 translocations are among the most common chromosomal abnormalities in acute leukemias (AL). The mixed-lineage leukemia (MLL) gene maps to human chromosome 11q23. More than 30 different reciprocal chromosomal bands are involved in MLL rearrangements, which result in fusion in-frame of MLL to the coding sequences from the partner genes (including self-fusion of MLL). To date, only half of partner genes have been cloned. Of note, up to 30-50% of MLL rearrangement detected at molecular level are missed by standard cytogenetics. Most of the previous studies of 11q23 abnormalities are from children, especially infant. Little is known about the clinical impact of different MLL rearrangement in adult AL. Moreover, in view of the discrepancies between cytogenetic data and molecular results, it is important to screen the MLL rearrangement in AL including cases without 11q23 abnormalities in order to adequately evaluate the clinical relevance of molecular subtypes of MLL rearrangement. Current data from childhood AL suggested that different 11q23 translocations responded differently to therapy. It is speculated that different fusion transcripts may be associated with a different expression level of drug resistance-related genes with different response to chemotherapeutic agents. The purposes of this project are to characterize the various fusion transcripts of MLL rearrangement by various molecular strategies, and then to correlate the molecular information with clinicopathologic, hematologic, and biologic features, as well as treatment outcome in order to determine the clinical relevance and prognostic impact of various MLL rearrangements. We will use Southern blot hybridization technique to determine the frequency of MLL rearrangement in adult AL and RT-PCR or multiplex PCR to characterize the fusion partners. We also try to identify the rare or currently uncharacterized partner genes by panhandle PCR and/or adaptor PCR. The expression levels of drug resistance genes including MDR-1 and GST-p will be quantified by real-time RT-PCR. The results of this study are expected to have important clinical implication. Characterization of MLL rearrangement will provide more precise diagnosis and serve as a target for monitoring minimal residual disease in the future, which in turn will help in designing more effective treatment protocols. With our large population of patients, good clinical care, and adequate laboratory support, we would be able to transfer the research results to clinical usefulness which will further contribute to the national health of our country. In addition, this study will provide a resource of additional far-reaching biological investigation such as leukemogenesis of MLL-associated AL.

Project ID:PG9103-0355
External Project ID:NHRI-EX91-9011SL