BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome-positive leukemias.
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 background, 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.
Jones
Dan
D
Departments of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, USA.
Luthra
Rajyalakshmi
R
Cortes
Jorge
J
Thomas
Deborah
D
O'Brien
Susan
S
Bueso-Ramos
Carlos
C
Hai
Seema
S
Ravandi
Farhad
F
de Lima
Marcos
M
Kantarjian
Hagop
H
Jorgensen
Jeffrey L
JL
D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D005784:Gene Amplification; D005838:Genotype; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D000074008:MDS1 and EVI1 Complex Locus Protein; D009154:Mutation; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011519:Proto-Oncogenes / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis*; D014157:Transcription Factors / Q000235:genetics
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C493728:RUNX1 protein, human; D014157:Transcription Factors; D016044:Fusion Proteins, bcr-abl