TY - JOUR
T1 - BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome positive leukemias
AU - Jones, Dan
AU - Luthra, Rajyalakshmi
AU - Cortes, Jorge
AU - Thomas, Deborah
AU - O'Brien, Susan
AU - Bueso-Ramos, Carlos
AU - Hai, Seema
AU - Ravandi, Farhad
AU - De Lima, Marcos
AU - Kantarjian, Hagop
AU - Jorgensen, Jeffrey L.
PY - 2008/12/15
Y1 - 2008/12/15
N2 - 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 with e1a2/p190 BCR-ABL cases, de novo e13-e14a2/p210 Ph+ lymphoid leukemia more frequently showed CML-type back-ground, had higher blast-normalized BCR-ABL transcript 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 up-regulation or gene amplification appears required for lymphoid transformation by p210 BCR-ABL.
AB - 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 with e1a2/p190 BCR-ABL cases, de novo e13-e14a2/p210 Ph+ lymphoid leukemia more frequently showed CML-type back-ground, had higher blast-normalized BCR-ABL transcript 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 up-regulation or gene amplification appears required for lymphoid transformation by p210 BCR-ABL.
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U2 - 10.1182/blood-2008-04-148791
DO - 10.1182/blood-2008-04-148791
M3 - Article
C2 - 18809762
AN - SCOPUS:58149382596
SN - 0006-4971
VL - 112
SP - 5190
EP - 5192
JO - Blood
JF - Blood
IS - 13
ER -