Specific extra chromosomes occur in a modal number dependent pattern in pediatric acute lymphoblastic leukemia

Heerema, Nyla A.; Raimondi, Susana C.; Anderson, James R.; Biegel, Jaclyn A.; Camitta, Bruce M.; Cooley, Linda D.; Gaynon, Paul S.; Hirsch, Betsy A.; Magenis, R. Ellen; McGavran, Loris; Patil, Shivanand R.; Pettenati, Mark J.; Pullen, Jeanette; Rao, Kathleen W.; Roulston, Diane; Schneider, Nancy R.; Shuster, Jonathan J.; Sanger, Warren G.; Sutcliffe, Maxine J.; Tuinen, P van; Watson, Michael S.; Carroll, Andrew J.

doi:10.1002/gcc.20451

Cited by 81 publications

(74 citation statements)

References 31 publications

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“…4 Accordingly, the number of IGH rearrangements per leukemia may be higher than in cases with disomy 14. Because only one rearrangement takes place per IGH allele per cell and clonal progeny, the maximum number of individual IGH rearrangements of such clones depends on the copy numbers of IGH alleles and therefore indirectly also on the copy numbers of chromosome 14.…”

Section: Introductionmentioning

confidence: 99%

“…1 The likelihood of relapse was found to correlate with the presence of specific trisomies, whose predictive value also depended on the respective treatment protocol. [2][3][4] The PCR-based determination of minimal residual disease (MRD) has evolved as the most relevant parameter for treatment stratification and is nowadays used worldwide. 1 Leukemia-associated immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements provide unique clone-specific molecular markers for MRD analysis.…”

Section: Introductionmentioning

confidence: 99%

“…Because only one rearrangement takes place per IGH allele per cell and clonal progeny, the maximum number of individual IGH rearrangements of such clones depends on the copy numbers of IGH alleles and therefore indirectly also on the copy numbers of chromosome 14. 4 A clone with disomy 14 can have a maximum of two unique rearrangements, whereas a clone with trisomy 14 could harbor either a maximum of three unique or two unique rearrangements together with a third that may share particular sequences with the one or the other. 17 The latter would derive from a duplicated, primarily rearranged IGH gene that continues to rearrange after the nondisjunction event.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2009

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2009

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“…Monosomies, on the other hand, are exceedingly rare (2,13). The pathogenetic consequences of the chromosomal gains remain poorly understood, but it generally is believed that gene dosage effects are of importance (2,14,15).…”

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confidence: 99%

Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia

Paulsson¹,

Forestier

Lilljebjörn³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

126

149

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High hyperdiploid acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. It is characterized by gain of chromosomes, typically +X, +4, +6, +10, +14, +17, +18, and +21, +21; little is known about additional genetic aberrations. Approximately 20% of the patients relapse; therefore it is clinically important to identify risk-stratifying markers. We used SNP array analysis to investigate a consecutive series of 74 cases of high hyperdiploid ALL. We show that the characteristic chromosomal gains are even more frequent than previously believed, indicating that karyotyping mistakes are common, and that almost 80% of the cases display additional abnormalities detectable by SNP array analysis. Subclonality analysis strongly implied that the numerical aberrations were primary and arose before structural events, suggesting that step-wise evolution of the leukemic clone is common. An association between duplication of 1q and +5 was seen (P = 0.003). Other frequent abnormalities included whole-chromosome uniparental isodisomies (wUPIDs) 9 and 11, gain of 17q not associated with isochromosome formation, extra gain of part of 21q, deletions of ETS variant 6 (ETV6), cyclin-dependent kinase inhibitor 2A (CKDN2A) and paired box 5 (PAX5), and PAN3 poly(A) specific ribonuclease subunit homolog (PAN3) microdeletions. Comparison of whole-chromosome and partial UPID9 suggested different pathogenetic outcomes, with the former not involving CDKN2A. Finally, two cases had partial deletions of AT rich interactive domain 5B (ARID5B), indicating that acquired as well as constitutional variants in this locus may be associated with pediatric ALL. Here we provide a comprehensive characterization of the genetic landscape of high hyperdiploid childhood ALL, including the heterogeneous pattern of secondary genetic events.

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“…20 PAX5 exon copy number Table S1) and normal tonsil DNA as calibrator, each point of the dilution series being tested six times. The same measurements were performed with two reference genes located on chromosomes 15 (B2M gene) and 16 (CNGB1 gene), because these two chromosomes are rarely modified in number in ALL, 21 using Ref15F and Ref15R primers for B2M and Ref16F and Ref16R primers for CNGB1 (Supplementary Table S1). The percentage of each PAX5 exon to the mean of Ref15 and Ref16 copy number was calculated.…”

Section: Graall-2003 and Graaph-2003 Clinical Protocolsmentioning

confidence: 99%

PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study

et al. 2009

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Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count. Leukemia (2009Leukemia ( ) 23, 1989Leukemia ( -1998 doi:10.1038/leu.2009; published online 9 July 2009 Keywords: BCP-ALL; oncogenesis; BCR-ABL1; PAX5; TCF3-PBX1 Introduction PAX5 (paired-box domain 5) is the guardian of the B-cell identity as stated in a recent review. 1 This transcription factor belongs to the family of paired-box domain transcription factors. 2 Its expression is initiated during early stages of B-cell differentiation beginning at the pro-B stage, 3 and is turned off to allow terminal B-cell differentiation. 4 The Pax5 homozygous deletion in murine models leads to the trans-or de-differentiation of B-cells into several other hematopoietic cell lineages. [5][6][7] PAX5 is thus involved both in the maintenance of B-cell identity and in the control of terminal B-cell differentiation.Deregulations and mutations of key differentiation factors are frequently found in lymphomas and leukemias. Translocations associated with hematologic malignancies involving PAX5 exemplify PAX5 dual function. On one hand, the t(9;14)(p13;q32) translocation brings the potent enhancer of the IGH gene close to the PAX5 promoter leading to an aberrant expression of a normal PAX5 protein. 8,9 This translocation is recurrent in small plasmacytoid B-cell lymphocytic lymphomas and diffuse large B-cell lymphomas. 10 It emphasizes the importance of PAX5 downregulation during terminal B-cell differentiation. 9 On the other hand, PAX5 translocations have also been associated with a block of early B-cell differentiation because the PAX5-ETV6 chimeric protein, product of the dic(9;12)(p13;p13), is associated with B-cell progenitor acute lymphoblastic leukemia (BCP-ALL). 11 Additional PAX5 fusion partner genes have been identified as HIPK1 (chromosomal band 1p13), 12-14 LOC392027 (7p12.1), 15 AUTS2 (7q11.1), 13 POM121 (7q11), 14 ELN (7q11), 16 JAK2 (9p24), 14 SLCO1B3 (12p12), 15 DACH1 (13q21), 14 PML (15q24), 17 ZNF5...

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Specific extra chromosomes occur in a modal number dependent pattern in pediatric acute lymphoblastic leukemia

Cited by 81 publications

References 31 publications

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

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

Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia

PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study

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