Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood
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 <i>POT1<...
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2021
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oai:doaj.org-article:ee2aebca508c48acb2ba60d602a819102021-11-11T17:03:18ZGermline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood10.3390/ijms2221115721422-00671661-6596https://doaj.org/article/ee2aebca508c48acb2ba60d602a819102021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11572https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067While 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 <i>POT1</i>, which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated <i>POT1</i> 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 <i>POT1</i> allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous <i>POT1</i> p.Q199* as well as <i>POT1</i> knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between <i>POT1</i> p.Q199* and telomeric dysregulation and highlight <i>POT1</i> germline deficiency as a predisposition to myeloid malignancies in childhood.Pia MichlerAnne SchedelMartha WitschasUlrike Anne FriedrichRabea WagenerJuha MehtonenTriantafyllia BrozouMaria MenzelCarolin WalterDalileh NabiGlen PearceMiriam ErlacherGudrun GöhringMartin DugasMerja HeinäniemiArndt BorkhardtFriedrich StölzelJulia HauerFranziska AuerMDPI AGarticleacute myeloid leukemiapediatrictrio sequencinggermline cancer predispositionPOT1shelterin complexBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11572, p 11572 (2021) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
acute myeloid leukemia pediatric trio sequencing germline cancer predisposition POT1 shelterin complex Biology (General) QH301-705.5 Chemistry QD1-999 |
| spellingShingle |
acute myeloid leukemia pediatric trio sequencing germline cancer predisposition POT1 shelterin complex Biology (General) QH301-705.5 Chemistry QD1-999 Pia Michler Anne Schedel Martha Witschas Ulrike Anne Friedrich Rabea Wagener Juha Mehtonen Triantafyllia Brozou Maria Menzel Carolin Walter Dalileh Nabi Glen Pearce Miriam Erlacher Gudrun Göhring Martin Dugas Merja Heinäniemi Arndt Borkhardt Friedrich Stölzel Julia Hauer Franziska Auer Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood |
| description |
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 <i>POT1</i>, which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated <i>POT1</i> 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 <i>POT1</i> allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous <i>POT1</i> p.Q199* as well as <i>POT1</i> knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between <i>POT1</i> p.Q199* and telomeric dysregulation and highlight <i>POT1</i> germline deficiency as a predisposition to myeloid malignancies in childhood. |
| format |
article |
| author |
Pia Michler Anne Schedel Martha Witschas Ulrike Anne Friedrich Rabea Wagener Juha Mehtonen Triantafyllia Brozou Maria Menzel Carolin Walter Dalileh Nabi Glen Pearce Miriam Erlacher Gudrun Göhring Martin Dugas Merja Heinäniemi Arndt Borkhardt Friedrich Stölzel Julia Hauer Franziska Auer |
| author_facet |
Pia Michler Anne Schedel Martha Witschas Ulrike Anne Friedrich Rabea Wagener Juha Mehtonen Triantafyllia Brozou Maria Menzel Carolin Walter Dalileh Nabi Glen Pearce Miriam Erlacher Gudrun Göhring Martin Dugas Merja Heinäniemi Arndt Borkhardt Friedrich Stölzel Julia Hauer Franziska Auer |
| author_sort |
Pia Michler |
| title |
Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood |
| title_short |
Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood |
| title_full |
Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood |
| title_fullStr |
Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood |
| title_full_unstemmed |
Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood |
| title_sort |
germline pot1 deregulation can predispose to myeloid malignancies in childhood |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/ee2aebca508c48acb2ba60d602a81910 |
| work_keys_str_mv |
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1718432211398557696 |