Research Papers:

Genetic and epigenetic characterization of hypodiploid acute lymphoblastic leukemia

Setareh Safavi, Linda Olsson, Andrea Biloglav, Srinivas Veerla, Molly Blendberg, Johnbosco Tayebwa, Mikael Behrendtz, Anders Castor, Markus Hansson, Bertil Johansson and Kajsa Paulsson _

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Oncotarget. 2015; 6:42793-42802. https://doi.org/10.18632/oncotarget.6000

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Setareh Safavi1, Linda Olsson1,2, Andrea Biloglav1, Srinivas Veerla3, Molly Blendberg1, Johnbosco Tayebwa1, Mikael Behrendtz4, Anders Castor5, Markus Hansson6, Bertil Johansson1,2, Kajsa Paulsson1

1Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden

2Department of Clinical Genetics, University and Regional Laboratories, Region Skåne, Lund, Sweden

3Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden

4Department of Pediatrics, Linköping University Hospital, Linköping, Sweden

5Department of Pediatrics, Skåne University Hospital, Lund University, Lund, Sweden

6Division of Hematology, Skåne University Hospital, Lund University, Lund, Sweden

Correspondence to:

Setareh Safavi, e-mail: [email protected]

Kajsa Paulsson, e-mail: [email protected]

Keywords: acute lymphoblastic leukemia, hypodiploidy, next generation sequencing, chromosomal instability

Received: August 26, 2015     Accepted: October 17, 2015     Published: October 30, 2015


Purpose: To investigate the genetic and epigenetic landscape of hypodiploid (<45 chromosomes) acute lymphoblastic leukemia (ALL).

Methods: Single nucleotide polymorphism array, whole exome sequencing, RNA sequencing, and methylation array analyses were performed on eleven hypodiploid ALL cases.

Results: In line with previous studies, mutations in IKZF3 and FLT3 were detected in near-haploid (25–30 chromosomes) cases. Low hypodiploidy (31–39 chromosomes) was associated with somatic TP53 mutations. Notably, mutations of this gene were also found in 3/3 high hypodiploid (40–44 chromosomes) cases, suggesting that the mutational patterns are similar in low hypodiploid and high hypodiploid ALL. The high hypodiploid ALLs frequently displayed substantial cell-to-cell variability in chromosomal content, indicative of chromosomal instability; a rare phenomenon in ALL. Gene expression analysis showed that genes on heterodisomic chromosomes were more highly expressed in hypodiploid cases. Cases clustered according to hypodiploid subtype in the unsupervised methylation analyses, but there was no association between chromosomal copy number and methylation levels. A comparison between samples obtained at diagnosis and relapse showed that the relapse did not arise from the major diagnostic clone in 3/4 cases.

Conclusion: Taken together, our data support the conclusion that near-haploid and low hypodiploid ALL are different with regard to mutational profiles and also suggest that ALL cases with high hypodiploidy may harbor chromosomal instability.

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