Parental Origin of Chromosomes 9 and 22 Involved in the Ph-Chromosome Formation
Authors: Winkowska Lucie , Skorepova Justina , Hovorkova Lenka , Bernatikova Hana , Sramkova Lucie , Trka Jan , Zaliova Marketa , Zuna Jan 
Published: December 2024

The parental origin of the Philadelphia (Ph) chromosome, derivative chromosome 22 resulting from a translocation with chromosome 9, has been a subject of interest in childhood leukemia research since the 1970s. Early studies, primarily based on cytogenetic techniques, suggested a significant bias in the parental origin of the chromosomes involved in this translocation. Specifically, some of the studies indicated that chromosome 9 was predominantly (or even exclusively) of paternal origin, while chromosome 22 of maternal. This proposition raised considerable debate in the field. However, genetic studies addressing this question have been very limited, with only two known smaller investigations from the 1990s focusing on the origin of either chromosome 9 or 22, but not both simultaneously.
We conducted a genetic analysis of 9 patients diagnosed with Ph-positive Acute Lymphoblastic Leukemia (ALL) or Chronic Myeloid Leukemia (CML), along with their parents. Our approach focused on identifying heterozygous Single Nucleotide Polymorphisms (SNPs) in the patients, in regions proximal to the BCR::ABL1 genomic fusion. In the heterozygous SNPs identified, we determined - using long-range PCR spanning the genomic breakpoint - which alleles originated from the fused chromosomes. By comparing these findings with parental genotypes, we were able to ascertain the parental origin of genes involved in the fusion, thereby determining the parental source of the chromosomes involved in the t(9;22) translocation. This research was approved by the institutional review board, informed consent was obtained from patients' parents, and all procedures were conducted in accordance with the Declaration of Helsinki.
Of the 9 patients analyzed, one case yielded inconclusive results where only the patient and his mother were available for genomic analyses. In the remaining 8 patients, we successfully identified the parental origin of the chromosomes involved in the BCR::ABL1 fusion. Four patients (50%) exhibited a pattern where the ABL1 gene (chromosome 9) was of paternal origin and the BCR gene (chromosome 22) was of maternal origin. Two patients (25%) showed the opposite pattern, with BCR of paternal origin and ABL1 of maternal origin. We also observed one patient where both genes were of maternal origin and another patient where both were of paternal origin.
To our knowledge, this study represents the first comprehensive molecular genetic analysis of the parental origin of chromosomes involved in the t(9;22) translocation. Our findings suggest a possible slight, non-significant preference for paternal chromosome 9 (ABL1) and maternal chromosome 22 (BCR) involvement in the Ph chromosome formation. However, our data unequivocally demonstrate that all possible combinations of parental origins are represented in the cohort. Despite the relatively small sample size, these results indicate that there is no strong bias towards a specific parental origin pattern in the formation of the Ph chromosome. This study provides valuable insights into the genetic dynamics of the BCR::ABL1 fusion in childhood leukemia and challenges previous notions of significant parental origin bias in Ph chromosome formation.
The work was supported by a grant from the Czech Health Research Council (NU21-03-00128), and by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - funded by the European Union - Next Generation EU.