Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles

M. G. Loudin; J. Wang; H. C. Eastwood Leung; S. Gurusiddappa; J. Meyer; G. Condos; D. Morrison; A. Tsimelzon; M. Devidas; N. A. Heerema; A. J. Carroll; S. E. Plon; S. P. Hunger; G. Basso; A. Pession; D. Bhojwani; W. L. Carroll; K. R. Rabin

doi:10.1038/leu.2011.128

Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles

M. G. Loudin, J. Wang, H. C. Eastwood Leung, S. Gurusiddappa, J. Meyer, G. Condos, D. Morrison, A. Tsimelzon, M. Devidas, N. A. Heerema, A. J. Carroll, S. E. Plon, S. P. Hunger, G. Basso, A. Pession, D. Bhojwani, W. L. Carroll, K. R. Rabin

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Abstract

Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-DS (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only 2 NDS cases (3.1%) (Fisher's exact P=0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters and enrichment of highly methylated genes for specific pathways and transcription factor-binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions.

Original language	English (US)
Pages (from-to)	1555-1563
Number of pages	9
Journal	Leukemia
Volume	25
Issue number	10
DOIs	https://doi.org/10.1038/leu.2011.128
State	Published - Oct 2011
Externally published	Yes

Bibliographical note

Funding Information:
We thank Susan Hilsenbeck, Jian Wang, Alexander Yu and Charlotte Ahern for biostatistical support; Daryl Scott for assistance with genomic quantitative PCR; Brandon Ballard for assistance with PCR and data analysis; Emanuela Giarin for assistance with AIEOP sample annotation; Richard Harvey for discussion and sharing preliminary bioinformatic analysis; and the patients and families whose participation made this work possible. This work was supported in part by a Bear Necessities Pediatric Research Foundation Grant; Children’s Cancer Research Foundation Grant; National Institutes of Health Pediatric Oncology Clinical Research Training Grant CA90433-06; Gillson Long-enbaugh Foundation; Kurt Groten Family Research Scholars’ Program (KRR); and the National Cancer Institute (NCI; SPEC U01 CA114762 and Genomics Core of the NYU Cancer Institute P30 CA016087, WLC).

Keywords

CRLF2
Down syndrome
JAK2
acute lymphoblastic leukemia
histone

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Loudin, M. G., Wang, J., Eastwood Leung, H. C., Gurusiddappa, S., Meyer, J., Condos, G., Morrison, D., Tsimelzon, A., Devidas, M., Heerema, N. A., Carroll, A. J., Plon, S. E., Hunger, S. P., Basso, G., Pession, A., Bhojwani, D., Carroll, W. L., & Rabin, K. R. (2011). Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles. Leukemia, 25(10), 1555-1563. https://doi.org/10.1038/leu.2011.128

Loudin, MG, Wang, J, Eastwood Leung, HC, Gurusiddappa, S, Meyer, J, Condos, G, Morrison, D, Tsimelzon, A, Devidas, M, Heerema, NA, Carroll, AJ, Plon, SE, Hunger, SP, Basso, G, Pession, A, Bhojwani, D, Carroll, WL & Rabin, KR 2011, 'Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles', Leukemia, vol. 25, no. 10, pp. 1555-1563. https://doi.org/10.1038/leu.2011.128

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title = "Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles",

abstract = "Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-DS (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only 2 NDS cases (3.1%) (Fisher's exact P=0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters and enrichment of highly methylated genes for specific pathways and transcription factor-binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions.",

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author = "Loudin, {M. G.} and J. Wang and {Eastwood Leung}, {H. C.} and S. Gurusiddappa and J. Meyer and G. Condos and D. Morrison and A. Tsimelzon and M. Devidas and Heerema, {N. A.} and Carroll, {A. J.} and Plon, {S. E.} and Hunger, {S. P.} and G. Basso and A. Pession and D. Bhojwani and Carroll, {W. L.} and Rabin, {K. R.}",

note = "Funding Information: We thank Susan Hilsenbeck, Jian Wang, Alexander Yu and Charlotte Ahern for biostatistical support; Daryl Scott for assistance with genomic quantitative PCR; Brandon Ballard for assistance with PCR and data analysis; Emanuela Giarin for assistance with AIEOP sample annotation; Richard Harvey for discussion and sharing preliminary bioinformatic analysis; and the patients and families whose participation made this work possible. This work was supported in part by a Bear Necessities Pediatric Research Foundation Grant; Children{\textquoteright}s Cancer Research Foundation Grant; National Institutes of Health Pediatric Oncology Clinical Research Training Grant CA90433-06; Gillson Long-enbaugh Foundation; Kurt Groten Family Research Scholars{\textquoteright} Program (KRR); and the National Cancer Institute (NCI; SPEC U01 CA114762 and Genomics Core of the NYU Cancer Institute P30 CA016087, WLC).",

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Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles

Abstract

Bibliographical note

Keywords

UN SDGs

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