Integrating Copy Number Data of 64 IAMP21 BCP-ALL Patients Narrows the Common Region of Amplification to 1.57 Mb

Overview

Journal Front Oncol

Specialty Oncology

Date 2023 Mar 13

PMID 36910655

Authors

Femke M Hormann

Alex Q Hoogkamer

Aurelie Boeree

Edwin Sonneveld

Gabriele Escherich

Monique L den Boer

Judith M Boer

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Intrachromosomal amplification of chromosome 21 (iAMP21) is a rare subtype of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). It is unknown how iAMP21 contributes to leukaemia. The currently known commonly amplified region is 5.1 Mb.

Methods: We aimed to narrow down the common region of amplification by using high resolution techniques. Array comparative genomic hybridization (aCGH) was used to determine copy number aberrations, Affymetrix U133 Plus2 expression arrays were used to determine gene expression. Genome-wide expression correlations were evaluated using Globaltest.

Results: We narrowed down the common region of amplification by combining copy number data from 12 iAMP21 cases with 52 cases from literature. The combined common region of amplification was 1.57 Mb, located from 36.07 to 37.64 Mb (GRCh38). This region is located telomeric from, but not including, , which is the locus commonly used to diagnose iAMP21. This narrow region, which falls inside the Down Syndrome critical region, includes 13 genes of which the expression of eight genes was significantly upregulated compared with 143 non-iAMP21 B-other cases. Among these, transcriptional repressor (also known as ) was the highest overexpressed gene (fold change = 4.2, FDR < 0.001) and most strongly correlated (R = 0.58) with iAMP21-related genome-wide expression changes.

Discussion: The more precise definition of the common region of amplification could be beneficial in the diagnosis of iAMP21 based on copy number analysis from DNA sequencing or arrays as well as stimulate functional research into the role of the included genes in iAMP21 biology.

Citing Articles

Acute lymphoblastic leukaemia.

Pagliaro L, Chen S, Herranz D, Mecucci C, Harrison C, Mullighan C Nat Rev Dis Primers. 2024; 10(1):41.

PMID: 38871740 DOI: 10.1038/s41572-024-00525-x.

References

Escherich G, Horstmann M, Zimmermann M, Janka-Schaub G . Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97. Leukemia. 2009; 24(2):298-308. DOI: 10.1038/leu.2009.249. View

Huber W, von Heydebreck A, Sultmann H, Poustka A, Vingron M . Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics. 2002; 18 Suppl 1:S96-104. DOI: 10.1093/bioinformatics/18.suppl_1.s96. View

Moorman A, Robinson H, Schwab C, Richards S, Hancock J, Mitchell C . Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003.... J Clin Oncol. 2013; 31(27):3389-96. DOI: 10.1200/JCO.2013.48.9377. View

den Boer M, van Slegtenhorst M, de Menezes R, Cheok M, Buijs-Gladdines J, Peters S . A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009; 10(2):125-34. PMC: 2707020. DOI: 10.1016/S1470-2045(08)70339-5. View

Soulier J, Trakhtenbrot L, Najfeld V, Lipton J, Mathew S, Avet-Loiseau H . Amplification of band q22 of chromosome 21, including AML1, in older children with acute lymphoblastic leukemia: an emerging molecular cytogenetic subgroup. Leukemia. 2003; 17(8):1679-82. DOI: 10.1038/sj.leu.2403000. View

Sinclair P, Parker H, An Q, Rand V, Ensor H, Harrison C . Analysis of a breakpoint cluster reveals insight into the mechanism of intrachromosomal amplification in a lymphoid malignancy. Hum Mol Genet. 2011; 20(13):2591-602. DOI: 10.1093/hmg/ddr159. View

van der Veer A, Waanders E, Pieters R, Willemse M, van Reijmersdal S, Russell L . Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood. 2013; 122(15):2622-9. PMC: 3795461. DOI: 10.1182/blood-2012-10-462358. View

Moorman A, Richards S, Robinson H, Strefford J, Gibson B, Kinsey S . Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood. 2006; 109(6):2327-30. DOI: 10.1182/blood-2006-08-040436. View

Polak R, Bierings M, van der Leije C, Sanders M, Roovers O, Marchante J . Autophagy inhibition as a potential future targeted therapy for ETV6-RUNX1-driven B-cell precursor acute lymphoblastic leukemia. Haematologica. 2018; 104(4):738-748. PMC: 6442983. DOI: 10.3324/haematol.2018.193631. View

10.

Sinclair P, Blair H, Ryan S, Buechler L, Cheng J, Clayton J . Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21. Haematologica. 2018; 103(4):634-644. PMC: 5865429. DOI: 10.3324/haematol.2017.172304. View

11.

Kamps W, van der Pal-de Bruin K, Veerman A, Fiocco M, Bierings M, Pieters R . Long-term results of Dutch Childhood Oncology Group studies for children with acute lymphoblastic leukemia from 1984 to 2004. Leukemia. 2009; 24(2):309-19. DOI: 10.1038/leu.2009.258. View

12.

Boer J, Steeghs E, Marchante J, Boeree A, Beaudoin J, Beverloo H . Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia. Oncotarget. 2016; 8(3):4618-4628. PMC: 5354859. DOI: 10.18632/oncotarget.13492. View

13.

Johnson W, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2006; 8(1):118-27. DOI: 10.1093/biostatistics/kxj037. View

14.

Duployez N, Boudry-Labis E, Decool G, Grzych G, Grardel N, Abou Chahla W . Diagnosis of intrachromosomal amplification of chromosome 21 (iAMP21) by molecular cytogenetics in pediatric acute lymphoblastic leukemia. Clin Case Rep. 2015; 3(10):814-6. PMC: 4614646. DOI: 10.1002/ccr3.357. View

15.

Li Y, Schwab C, Ryan S, Papaemmanuil E, Robinson H, Jacobs P . Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature. 2014; 508(7494):98-102. PMC: 3976272. DOI: 10.1038/nature13115. View

16.

Baughn L, Meredith M, Oseth L, Smolarek T, Hirsch B . SH2B3 aberrations enriched in iAMP21 B lymphoblastic leukemia. Cancer Genet. 2018; 226-227:30-35. DOI: 10.1016/j.cancergen.2018.05.004. View

17.

Johnson R, Weinberg O, Cascio M, Dahl G, Mitton B, Silverman L . Cytogenetic Variation of B-Lymphoblastic Leukemia With Intrachromosomal Amplification of Chromosome 21 (iAMP21): A Multi-Institutional Series Review. Am J Clin Pathol. 2015; 144(1):103-12. DOI: 10.1309/AJCPLUYF11HQBYRB. View

18.

Ryan S, Matheson E, Grossmann V, Sinclair P, Bashton M, Schwab C . The role of the RAS pathway in iAMP21-ALL. Leukemia. 2016; 30(9):1824-31. PMC: 5017527. DOI: 10.1038/leu.2016.80. View

19.

Harrison C, Moorman A, Schwab C, Carroll A, Raetz E, Devidas M . An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome. Leukemia. 2013; 28(5):1015-21. PMC: 4283797. DOI: 10.1038/leu.2013.317. View

20.

den Boer M, Harms D, Pieters R, Kazemier K, Gobel U, Korholz D . Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia. J Clin Oncol. 2003; 21(17):3262-8. DOI: 10.1200/JCO.2003.11.031. View