Genomic level analyses (tiling arrays and high throughput sequencing) have shown the extent of transcription of non-coding RNA. Estimates vary- about 1-2% of the genome produces protein-coding RNA transcripts; while 30-50% of the genome is transcribed into non-coding transcripts! We are very interested to find out whether non-coding RNA, including but not limited to microRNAs, are important in the pathogenesis of leukemia. We are actively pursuing these studies, and with the help of bioinformatics collaborators and clinical colleagues in Los Angeles and elsewhere, are making significant progress towards defining non-coding RNAs in both pathologic states such as leukemia and lymphoma, but also in normal development. These studies involve a significant computational component, and we are actively working with bioinformatics and computational biology experts to resolve these important questions in how to recognize novel transcripts.
The recently discovered novel class of non-coding RNA, termed long intergenic non-coding RNA (lincRNA), play important roles in gene expression regulation, development and cancer. However, their roles in cancer have only begun to be explored. We have initiated an ambitious research study, using gene expression profiling to characterize the expression of lincRNA in B-lymphoblastic leukemia (B-ALL). We have discovered a set of lincRNAs that are differentially regulated in leukemia and particularly in poor-prognosis B-ALL with translocations of the mixed lineage leukemia (MLL) gene. One of these lincRNAs, BALR-2, was chosen for further study based on their correlation with clinicopathologic parameters and conservation of their genomic loci in mammals. We have made significant progress in understanding the cellular functions of BALR-2, finding that it promotes survival of leukemic cells. BALR-2 knockdown leads to activation of apoptosis pathways through the pro-apoptotic protein BIM. Further studies to characterize the role of BALR-2 in malignant transformation of hematopoietic cells and its utility as a therapeutic are actively being pursued in the laboratory.
Moreover, we are now beginning to study additional long non-coding RNA molecules in B-cell development and leukemia. We recently published a paper characterizing the role of BALR-6 in MLL-translocated leukemia; and we are now investigating the long non-coding RNA, CASC15, in B-cell leukemia and B-cell development.