3′ BCR recombines with IGL locus in BCRABL–positive Philadelphia‐negative chronic myeloid leukemia

Abstract

We have isolated the 3' BCR breakpoint junction of a complex BCR-ABL1 rearrangement found in leukemic cells with a cytogenetically normal karyotype, and the corresponding germline fragment that spanned the 3' BCR recombination site. Fluorescence in situ hybridization localized the 3' BCR recombination site to 22q11, about 350-600 kb proximal to BCR. Restriction map and DNA sequence comparisons indicated that 3' M-Bcr had recombined at a site within the variable region (Itv Region IV) of the immunoglobulin lambda (IGL) locus. Somatic rearrangement of DNA sequences (variable, joining, and constant regions) within the IGL locus, as in other Ig and TCR loci, represents the basis for human antibody diversity. Misrecombination of these somatically rearranging sites has been associated with chromosomal rearrangements in lymphoid leukemia and lymphoma, but there are no previous descriptions of IGL involvement in genomic aberrations associated with myeloid leukemia. Genes Chromosomes Cancer 26:366-371, 1999.

A full-length and potentially active LINE element is integrated polymorphically within the IGL locus in a genomically unstable region of chromosome 22

“…The 6053 bp of DNA sequence, when submitted to BLASTN (http://www.ncbi.nlm.nih.gov/blast/blast.cgi, 5-4-01), was not present in the database but showed complete and intact alignment to various L1 elements. The L1 element polymorphism identified here was previously determined to map within the IGL locus (Benjes et al 1999) and therefore designated L1 IGL . L1 IGL showed highest homology to a full-length L1 element inserted into chromosome Y (bacterial artificial chromosome clone RP11-65E7, ACD10081-41/AC010081, nucleotides 19478-13446) and a full-length element inserted into the NOD1 gene on chromosome 7p14-p15 (AF149774.1/HSNOD1G2, nucleotides 12145-18160), with 99.58% and 99.54% nucleotide identities, respectively.…”

“…Southern blot analysis of genomic DNA and polymerase chain reaction products High molecular weight DNA isolated from leukemic cells or peripheral blood (PB) cells from normal consenting donors was digested with restriction enzymes, electrophoresed, Southern-blotted, and hybridized with 32 P-dCTP-oligolabeled probes and methods previously described (Benjes et al 1999). Polymerase chain reaction (PCR) products were electrophoresed, Southern-blotted, and hybridized as for high-molecular-weight DNA.…”

“…2; Morris et al 1986). We have shown that the 3′ part of BCR has recombined at a site on chromosome 22 within the immunoglobulin lambda locus (IGL) intervening variable-gene region IV (Itv-Region IV), between two variable genes Vλ3-4 and Vλ5-4 (Benjes et al 1999). A genomic probe, initially used to confirm the authenticity of the cloned IGL/3′BCR breakpoint junction fragment and to isolate the corresponding IGL germline segment that spans the 3′BCR recombination site, detected an insertion polymorphism in normal control DNA.…”

“…A genomic probe, initially used to confirm the authenticity of the cloned IGL/3′BCR breakpoint junction fragment and to isolate the corresponding IGL germline segment that spans the 3′BCR recombination site, detected an insertion polymorphism in normal control DNA. Two allelic variants were identified that exhibited stable Mendelian inheritance and mapped ~3 kb 5′ of the IGL breakpoint (Benjes et al 1999). Here, we describe our molecular characterization of this polymorphic site and report the identification of a new and potentially active L1 element that maps within the IGL locus immediately upstream of BCR and within a wider region of chromosome 22q11.2 that is particularly prone to genomic instability associated with many inherited and malignant genetic conditions.…”

“…1a, probe c; Benjes et al 1999). To determine more specifically the insertion site of the identified insertion polymorphism, genomic DNA of individuals with genotypes A 1 A 1 , A 1 A 2 , and A 2 A 2 was digested with the enzymes BglII, BamHI, HindIII, and EcoRI and Southern-blotted.…”