Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis

• Published in: Blood 2001-06, Vol.97 (11), p.3581-3588
• Main Authors: Kolomietz, Elena, Al-Maghrabi, Jaudah, Brennan, Shawn, Karaskova, Jana, Minkin, Solomon, Lipton, Jeffrey, Squire, Jeremy A.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Biological and medical sciences; Bone Marrow Transplantation; Chromosome Aberrations; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 9; Core Binding Factor beta Subunit; Cytogenetic Analysis; DNA-Binding Proteins - genetics; Female; Fusion Proteins, bcr-abl - genetics; Gene Deletion; Hematologic and hematopoietic diseases; Humans; In Situ Hybridization, Fluorescence; Leukemia - genetics; Leukemia - mortality; Leukemia - therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Myosin Heavy Chains - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Prognosis; Recurrence; Sequence Analysis, DNA; Survival Rate; Transcription Factor AP-2; Transcription Factors - genetics; Translocation, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V97.11.3581

BCR/ABL fluorescent in situ hybridization study of chronic myeloid leukemia (CML) and Philadelphia+(Ph+) acute lymphoid leukemia (ALL) indicated that approximately 9% of patients exhibited an atypical hybridization pattern consistent with a submicroscopic deletion of the 5′ region ofABL and the 3′ region of the BCR genes on the 9q+ chromosome. The CML patients with deletions had a shorter survival time and a high relapse rate following bone marrow transplant. Since deletions are associated with both Ph+CML and ALL, it seemed probable that other leukemia-associated genomic rearrangements may also have submicroscopic deletions. This hypothesis was confirmed by the detection of deletions of the 3′ regions of theCBFB and the MLL genes in AML M4 patients with inv(16) and in patients with ALL and AML associated withMLL gene translocations, respectively. In contrast, analysis of the AML M3 group of patients and AML M2 showed that similar large deletions were not frequently associated with the t(15;17) or t(8;21) translocations. Analysis of sequence data from each of the breakpoint regions suggested that large submicroscopic deletions occur in regions with a high overall density of Alu sequence repeats. These findings are the first to show that the process of deletion formation is not disease specific in leukemia and also implicate that the presence of repetitive DNA in the vicinity of breakpoint regions may facilitate the generation of submicroscopic deletions. Such deletions could lead to the loss of one or more genes, and the associated haploinsufficiency may result in the observed differences in clinical behavior.