Overexpression of chromatin remodeling and tyrosine kinase genes in iAMP21-positive acute lymphoblastic leukemia

Abstract

Intrachromosomal amplification of chromosome 21 (iAMP21) is a cytogenetic subtype associated with relapse and poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). The biology behind the high relapse risk is unknown and the aim of this study was to further characterize the genomic and transcriptional landscape of iAMP21. Using DNA arrays and sequencing, we could identify rearrangements and aberrations characteristic for iAMP21. RNA sequencing revealed that only half of the genes in the minimal region of amplification (20/45) were differentially expressed in iAMP21. Among them were the top overexpressed genes (p < 0.001) in iAMP21 vs. BCP ALL without iAMP21 and three candidate genes could be identified, the tyrosine kinase gene DYRK1A and chromatin remodeling genes CHAF1B and SON. While overexpression of DYRK1A and CHAF1B is associated with poor prognosis in malignant diseases including myeloid leukemia, this is the first study to show significant correlation with iAMP21-positive ALL.

Keywords:

• Acute lymphoblastic leukemia
• iAMP21
• MP-WGS
• transcriptome sequencing
• gene expression analysis

Acknowledgements

We acknowledge the late professor Dan Grandér (Department of Oncology-Pathology, Karolinska Institutet), deceased in October 2017, for substantial contributions to sample collection and study design. We acknowledge the National Genomics Infrastructure and Science for Life Laboratory for assistance with massively parallel sequencing, the Uppsala Multidisciplinary Center for Advanced Computational Science for access to the UPPMAX computational infrastructure. We are grateful for the excellent technical support from laboratory technicians Malin Hertzman and Tekleweini Tadesse.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by grants from Barncancerfonden (the Swedish Childhood Cancer Foundation), the Mary Béve Foundation for Pediatric Cancer Research and Karolinska Institutet.