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. 2015 Dec 15;6(40):42793-802.
doi: 10.18632/oncotarget.6000.

Genetic and epigenetic characterization of hypodiploid acute lymphoblastic leukemia

Setareh Safavi  1 , Linda Olsson  1   2 , Andrea Biloglav  1 , Srinivas Veerla  3 , Molly Blendberg  1 , Johnbosco Tayebwa  1 , Mikael Behrendtz  4 , Anders Castor  5 , Markus Hansson  6 , Bertil Johansson  1   2 , Kajsa Paulsson  1
Affiliations

Genetic and epigenetic characterization of hypodiploid acute lymphoblastic leukemia

Setareh Safavi et al. Oncotarget. .

Abstract

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.

Conclusions: 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.

Keywords: acute lymphoblastic leukemia; chromosomal instability; hypodiploidy; next generation sequencing.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Summary of the genomic landscape of hypodiploid acute lymphoblastic leukemia (ALL)
Chromosomal profiles of near-haploid (NH), low hypodiploid (HoL) and high hypodiploid (HoH) ALL are shown, including previously known mutational targets in black and mutational targets identified or confirmed in this investigation in red.
See this image and copyright information in PMC

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