Jumping translocations: Short telomeres or pathogenic TP53 variants as underlying mechanism in acute myeloid leukemia and myelodysplastic syndrome?

Abstract

Chromosomal rearrangements involving one donor chromosome and two or more recipient chromosomes are called jumping translocations. To date only few cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with jumping translocations have been described and the underlying mechanisms remain unclear. Here, we analyzed 11 AML and 5 MDS cases with jumping translocations. The cases were analyzed by karyotyping, FISH, telomere length measurement, and next-generation sequencing with an AML/MDS gene panel.Cases with jumping translocations showed significantly (P < .01) shorter telomeres in comparison to healthy age-matched controls. Additional neo-telomeres were found in two cases. In total, eight cases showed recipient chromosomes with a breakpoint in the centromeric region all of them harboring a pathogenic variant in the TP53 gene (n = 6) and/or a loss of TP53 (n = 5). By contrast, no pathogenic variant or loss of TP53 was identified in the six cases showing recipient chromosomes with a breakpoint in the telomeric region. In conclusion, our results divide the cohort of AML and MDS cases with jumping translocations into two groups: the first group with a telomeric breakpoint of the recipient chromosome is characterized by short telomeres and a possibly telomere-based mechanism of chromosomal instability formation. The second group with a centromeric breakpoint of the recipient chromosome is defined by mutation and/or loss of TP53. We, therefore, assume that both critically short telomeres as well as pathogenic variants of TP53 influence jumping translocation formation.

Jumping Translocation in a Patient with Acute Leukemia and Fatal Evolution

“…As shown by previous case series, the involvement of receptor chromosomes is highly variable, but the aforementioned receptor chromosomes have been described in other patients, especially chromosomes 13 and 15 [2][3][4][5] In our patient, mutations affecting genes involved in RNA splicing and DNA methylation (ASXL1, SF3B1, SRSF2) were observed [10]. These have been described as frequent "driver" mutations that appear at the beginning of the disease, both in MDS and AML [11,12].…”

“…Behrens et al [2] have also observed that in the receptor chromosomes there is generally a cut point in the pericentromeric or peritelomeric regions, but rarely outside of these locations. In line with other publications, they found significant shortening of telomeres in patients with JT, compared to controls in age-matched groups.…”

“…Furthermore, in the cases of JT where the cut point of the receptor chromosomes was in the pericentromeric region, there was a pathogenic variant in TP53 (mutations and/or deletions), but not in those with the cut point in the telomeric region. Therefore, Behrens et al proposed that the pathogenic variants of TP53 may have a role in the formation of JT [2].…”

“…Bone marrow showed 22.8% blasts of myeloid phenotype (CD34 + , CD13 + , CD33 + , HLA-DR + , CD117 + , and CD64 + ). In the cytogenetic study, a JT was found, with the following karyotype: 46,XY,der(13)t(1;13) (q11;p11) [12]/46,XY,der(15)t(1;15)(q11;p11)[3]/46,X,-Y,+del(1)(p12) [3]/46,X,der(Y) t(Y;1)(q12;q11) [2]. A FISH study with a probe that hybridizes to the TP53 gene was performed, and no deletion of this gene was observed in any of the cells analyzed (200).…”

“…Other donor chromosomes involved are chromosomes 3, 11, 15, and 21. Poor clinical course and disease progression have been observed in patients with myeloid neoplasms carrying JT, although the prognostic implications that these aberrancies may have are not known in depth [2].…”