Submitted April 1, 2008
Accepted August 27, 2008
BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome-positive leukemias
Dan Jones*, Rajyalakshmi Luthra, Jorge Cortes, Deborah Thomas, Susan O'Brien, Carlos Bueso-Ramos, Seema Hai, Farhad Ravandi, Marcos de Lima, Hagop Kantarjian, and Jeffrey L Jorgensen
Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: dajones{at}mdanderson.org.
It remains unresolved how different BCR-ABL transcripts differentially drive lymphoid and myeloid proliferation in Philadelphia chromosome-positive (Ph+) leukemias. We compared BCR-ABL transcript type and level with kinase domain (KD) mutation status, genotype, and phenotype in 1855 Ph+ leukemias. Compared to ela2/p190 BCR-ABL cases, de novo e13-e14a2/p210 Ph+ lymphoid leukemia more frequently showed CML-type background, had higher blast-normalized BCR-ABL transript levels, and more frequent persistent BCR-ABL transcript in the absence of detectable lymphoblasts. Secondary lymphoid blast transformation of CML was exclusively due to e13/e14a2/p210 BCR-ABL but was associated, at a much higher level than p210 myeloid transformation, with acquisition of new KD mutations and/or Ph genomic amplification. In contrast, myeloid blast transformation was more frequently accompanied by new acquisition of acute myeloid leukemia-type chromosomal aberrations, particularly involving the EVI1 and RUNX1 loci. Therefore, higher kinase activity by mutation, transcriptional upregulation or gene amplification appears required for lymphoid transformation by p210 BCR-ABL.
