Chimeric RNA as a diagnostic marker of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) Using paired-end tag sequencing of RNA transcripts from chronic lymphocytic leukemia (CLL) patients, researchers at the University of Michigan have identified nine chimeric RNAs expressed in CLL patients. Among these chimeric RNAs are two recurrent and reciprocal chimeric RNA that was detected at a frequency of greater than 95% in CLL samples but not in paired normal samples, benign lymphocytes and other forms of cancers. There are no underlying DNA-level or chromosome rearrangements that account for the presence of chimeric RNAs in CLL samples. In addition, the reciprocal chimeric RNAs were detected in CLL patients irrespective of several gene mutations status associated with the disease. These recurrent and reciprocal RNA chimeras may potentially be used as a highly specific CLL diagnostic marker that is present at high frequency in CLL patients and may address the diagnostic challenges that come with the heterogenous nature of CLL.
RNA chimeras and cancer Recurrent gene fusions that arise from chromosomal rearrangements are common features of human tumors. The recent advances in deep sequencing of RNA transcripts isolated from tumor samples from cancer patients have allowed the identification of functional chimeric RNA from gene fusions associated with several types of cancer. More recently, chimeric RNA transcripts without an underlying DNA-level or chromosomal rearrangements have been identified and associated with some forms of cancer. The prevailing view is that the protein products of the chimeric RNA most often have abnormal functions that confer growth advantage that is often causally related to the uncontrolled growth of the cancer cells. Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world, occurring mostly in elderly people and with an incidence rate estimated to be 5.12 per 100,000 and death rate of 1.1 per 100,000. CLL is a type of white blood cell cancer that is characterized by a clonal proliferation and accumulation of functionally impaired B cells in the blood, bone marrow, spleen and lymph nodes. A similar form of CLL, called small lymphocytic lymphoma (SLL), is histologically and immunophenotypically the same as CLL with the primary tumor cells found in the lymph nodes. CLL and SLL are considered to be different forms of the same disease. CLL/SLL is a remarkably heterogenous disorder that is evident in the many underlying gene mutations and variations in the expression of serum and cell markers. In addition, recurrent balanced chromosomal rearrangements of oncogenes in CLL/SLL are rare and no unifying mutations or molecular characteristic have been identified.
Applications • Diagnostic marker for CLL • Therapeutic target with potentially broad role in CLL development Advantages • Highly specific to CLL • Easy and high frequency of detection that bypasses the genetic heterogeneity of CLL • First RNA chimeric marker associated with leukemia