Chromosome 14 copy number-dependent IGH gene rearrangement patterns in high hyperdiploid childhood B-cell precursor ALL: implications for leukemia biology and minimal residual disease analysis

Abstract

Childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL) is generally a clonal disease in which the number of IGH rearrangements per cell does not exceed the number of the IGH alleles on chromosome 14. Consequently, monoclonal high hyperdiploid (HeH) cases with a trisomy 14 can harbor three rearrangements, a pattern that otherwise may be misinterpreted to be oligoclonal. Oligoclonal IGH rearrangements, on the other hand, may be instable at relapse and should therefore not be used for minimal residual disease analysis. We thus investigated the association between IGH allele copy numbers and the IGH rearrangement patterns in 90 HeH BCP ALL with either two (13%) or three copies (87%) of chromosome 14. HeH cases (44%) had an oligoclonal IGH rearrangement pattern, but true oligoclonalityFafter correction for the respective copy number of IGH allelesFwas only 16%. Monoclonal and oligoclonal HeH cases had predominantly V H to preexisting DJ H recombinations, a finding that contrasts with oligoclonal cases of other major genetic BCP ALL subgroups in which V H replacements prevail. We conclude that for the precise assessment and correct interpretation of clonality patterns in BCP ALL, the IGH allele copy number has to be taken into consideration.

Clinical significance of productive immunoglobulin heavy chain gene rearrangements in childhood acute lymphoblastic leukemia

“…Previous studies have documented a decreased relapse rate in patients with ALL with oligoclonality, although in other reports a link of oligoclonality with patient survival was not verified [33,34]. Previous studies support that oligoclonality is frequently associated with polysomy of chromosome 14 and immature immunogenotypic features of the leukemic clone [35][36][37]. In contrast, in our series extra copies of chromosome 14 were not detected.…”

Immunoglobulin and T Cell Receptor Gene High-Throughput Sequencing Quantifies Minimal Residual Disease in Acute Lymphoblastic Leukemia and Predicts Post-Transplantation Relapse and Survival

“…19–21 In addition, as discussed above, clonal switch at the IGH locus may limit its usefulness as a post-therapy disease marker, 23, 31 although IGH oligoclonality appears to be less common in adult patients than in pediatric patients. 34 Fortunately, other genetic targets for clonotyping ALL exist which may overcome the limitations imposed by lack of stable IGH clonotypes, including partial IGH-DJ rearrangements, which likely capture an additional 10–30% of patients, 20, 22, 23 or rearrangements of the IGL or IGK loci which may be detectable in up to 50% of patients in some series. 19 Additionally, TCRB, TCRD or TCRG loci are rearranged in a significant percentage of both B-cell (30–50%) and T-cell (up to 75%) ALL isolates.…”

“…19–21 Roughly 10–30% of B-ALL isolates lacking a stable IGH-VDJ rearrangement have a stable and unique IGH-DJ partial rearrangement detectable. 20, 22, 23 Other immunoreceptor loci may also undergo rearrangement in precursor B and T lymphoblasts. TCRB rearrangements have been detected in up to 35% of B-ALLs and more than 75% of T-ALLs, 24, 25 while the TCRD and TCRG loci are clonally rearranged in a significant minority of B-ALL isolates.…”

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling

“…26 Hybridization to Affymetrix GeneChip Human Mapping 250K Nsp and 250K Sty arrays (n ϭ 6) or to Affymetrix Genome-Wide Human SNP Array 6.0 (n ϭ 7) were performed by imaGenes.…”