Document Detail


Analysis of clonal rearrangements of the Ig heavy chain locus in acute leukemia.
MedLine Citation:
PMID:  8652839     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Clonal rearrangements of the Ig heavy chain (IGH) locus occur in nearly all cases of B-cell precursor acute leukemia (BCP-ALL). Some of these rearrangements may be detected by polymerase chain reaction (PCR) using VH gene framework III (FRIII) and JH consensus primers. However, about 20% of BCP-ALLs fail to amplify with this technique. To determine the causes of these PCR failures and to investigate any possible association with specific subgroups of disease, we analyzed 72 acute leukemias of defined immunophenotype and cytogenetics, comparing FRIII with VH-family leader-specific PCR methods and Southern blotting. Of 37 BCP-ALL cases, 6 (16.2%) failed totally to amplify with FRIII and JH primers. None of these cases amplified with VH leader primers. Additionally, all cases retained germline VH6 genes and 5 of 11 rearranged alleles amplified with a consensus DH primer, indicating that these rearrangements represented biallelic DH-JH recombinations. Among the 6 FRIII and VH leader PCR-negative BCP-ALL cases, there was no common immunophenotype or consistent cytogenetic abnormality, although all showed structural chromosomal abnormalities and 3 of 5 successfully karyotyped had abnormalities of chromosome 12p. 13 cases with t(9;22)(q34;q11) Philadelphia chromosome-positive [Ph+]) and IGH rearrangements (9 BCP-ALL and 4 biphenotypic cases) were also analyzed. Of 23 rearranged IGH alleles, 19 (82%) were positive by FRIII PCR, and all 4 remaining alleles were amplified by VH leader primers. Use of the leader primers in these Ph+ cases also detected 3 additional clonal rearrangements that were not anticipated from Southern blotting; such unexpected bands were not observed in 21 other Ph- cases. The additional bands represented "new" and unrelated VH rearrangements rather than VH-VH replacement events. We conclude that biallelic DHJH rearrangements occur in a subgroup of BCP-ALL; in these cases, the activation of the full VHDHJH recombination mechanism had not occurred. Therefore, these cases of BCP-ALL were arrested at an early stage of B-cell differentiation. In contrast, all Ph+ BCP-ALLs and biphenotypic acute leukemias, which may represent the transformation of multipotent hemopoietic stem cells, had undergone VHDHJH recombination. Of 9 Ph+ BCP-ALL cases, 3 also showed ongoing VHDHJH rearrangement, reflecting the persistent expression of the VHDHJH recombinase. Finally, sequence analysis of 33 rearranged VHDHJH genes showed that only 3 including 2 Ph+ BCP-ALL maintained an intact open-reading frame. Loss of the open-reading frame occurred not only because of out-of-frame VHDH and DHJH joining, but also because of VH gene mutation and deletion. These data show that most BCP-ALLs may represent the neoplastic transformation of BCPs destined to die in the bone marrow.
Authors:
S E Height; G J Swansbury; E Matutes; J G Treleaven; D Catovsky; M J Dyer
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Blood     Volume:  87     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  1996 Jun 
Date Detail:
Created Date:  1996-07-31     Completed Date:  1996-07-31     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  5242-50     Citation Subset:  AIM; IM    
Affiliation:
Academic Department of Haematology and Cytogenetics, Haddow Laboratories, Institute of Cancer Research-Royal Marsden Hospital, Sutton, Surrey, UK.
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MeSH Terms
Descriptor/Qualifier:
Acute Disease
Adolescent
Adult
Aged
B-Lymphocytes / pathology
Base Sequence
Cell Transformation, Neoplastic / genetics
Child
Child, Preschool
Clone Cells / chemistry
DNA, Neoplasm / analysis
Female
Gene Rearrangement, B-Lymphocyte, Heavy Chain*
Genes, Immunoglobulin*
Humans
Immunoglobulin Heavy Chains / genetics*
Leukemia / classification,  genetics*,  pathology
Leukemia, B-Cell / genetics,  pathology
Male
Middle Aged
Molecular Sequence Data
Neoplastic Stem Cells / chemistry
Philadelphia Chromosome
Polymerase Chain Reaction
Sequence Alignment
Chemical
Reg. No./Substance:
0/DNA, Neoplasm; 0/Immunoglobulin Heavy Chains

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