Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 21, Pages -Publisher
MDPI
DOI: 10.3390/ijms222111572
Keywords
acute myeloid leukemia; pediatric; trio sequencing; germline cancer predisposition; POT1; shelterin complex
Funding
- ERC [85222]
- ERA Per Med.JTC 2018 GEPARD
- Sonnenstrahl e.V.
- Mildred-Scheel-Nachwuchszentrum (MSNZ)-TU Dresden
- Deutsche Krebsstiftung
- Deutsche Jose Carreras LeukamieStiftung e.V.
- Gesellschaft fur Paediatrische Onkologie und Haematologie e.V. [PS (01/2020)]
- Forschungskommission of Heinrich-HeineUniversitat Dusseldorf [2020-28]
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This study identified a novel germline stop-gain variant in the shelterin complex gene POT1 in a child with acute myeloid leukemia, which resulted in increased DNA damage and chromosomal instabilities. The variant also led to telomeric elongation and highlighted the predisposition to myeloid malignancies in childhood caused by POT1 germline deficiency.
While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregulation of this process is tightly linked to malignant transformation and cancer. Here, we present the novel finding of a germline stop-gain variant (p.Q199*) in the shelterin complex gene POT1, which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated POT1 display increased DNA damage and chromosomal instabilities compared to the wildtype counterpart. Protein and mRNA expression analyses in the primary patient cells further confirm that, physiologically, the variant leads to a nonfunctional POT1 allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous POT1 p.Q199* as well as POT1 knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between POT1 p.Q199* and telomeric dysregulation and highlight POT1 germline deficiency as a predisposition to myeloid malignancies in childhood.
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