Congenital Aneuploidy in Klinefelter Syndrome with B-Cell Acute Lymphoblastic Leukemia Might Be Associated with Chromosomal Instability and Reduced Telomere Length

Simple Summary Klinefelter syndrome (KS) is a rare congenital aneuploidy characterized by inherited gain of one X chromosome (XXY). KS is associated with higher susceptibility to the development of cancer. Somatic acquired chromosomal aberrations and chromosomal instability are hallmarks of cancer and leukemia but little is known about the cellular mechanisms involved. The conducted research aimed to identify genomic mechanisms involved in chromosomal evolution mechanisms important for leukemic development. In the leukemic blasts of a patient with KS and B-cell acute lymphoblastic leukemia (B-ALL), we identified additional acquired chromosomal aberration and a significant reduction in the length of the chromosomal ends, i.e., telomeres. A literature review of KS patients with B-ALL revealed that the majority of these patients had acquired two or more additional chromosomal aberrations at B-ALL diagnosis. These data indicate that enhanced reduction in telomere length might be associated with chromosomal instability and may serve as a future target for therapy or prevention. Rare congenital aneuploid conditions such as trisomy 13, trisomy 18, trisomy 21 and Klinefelter syndrome (KS, 47,XXY) are associated with higher susceptibility to developing cancer compared with euploid genomes. Aneuploidy frequently co-exists with chromosomal instability, which can be viewed as a "vicious cycle" where aneuploidy potentiates chromosomal instability, leading to further karyotype diversity, and in turn, paving the adaptive evolution of cancer. However, the relationship between congenital aneuploidy per se and tumor initiation and/or progression is not well understood. We used G-banding analysis, array comparative genomic hybridization analysis and quantitative fluorescence in situ hybridization for telomere length analysis to characterize the leukemic blasts of a three-year-old boy with KS and B-cell acute lymphoblastic leukemia (B-ALL), to gain insight into genomic evolution mechanisms in congenital aneuploidy and leukemic development. We found chromosomal instability and a significant reduction in telomere length in leukemic blasts when compared with the non-leukemic aneuploid cells. Reviewing published cases with KS and B-ALL revealed 20 additional cases with B-ALL diagnostic cytogenetics. Including our present case, 67.7% (14/21) had acquired two or more additional chromosomal aberrations at B-ALL diagnosis. The presented data indicate that congenital aneuploidy in B-ALL might be associated with chromosomal instability, which may be fueled by enhanced telomere attrition.