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The Role of ETV6 Germline Mutations in B Cell Development and Predisposition to Leukemia
Başlık:
The Role of ETV6 Germline Mutations in B Cell Development and Predisposition to Leukemia
Yazar:
Kirkpatrick, Gregory D., author.
ISBN:
9780438003064
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (111 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Jorge Di Paola; Chris Porter Committee members: Patricia Ernst; Arthur Gutierrez-Hartmann; Craig Jordan; Alisa Lee-Sherick.
Özet:
Acute lymphoblastic leukemia is the most common cancer in children, and the tumor suppressor ETV6 has long been associated with the disease, most commonly as part of the ETV6-RUNX1 translocation. Our group and others recently reported a heritable disease syndrome of thrombocytopenia and predisposition to leukemia in families carrying germline mutations in ETV6, but the mechanisms by which these mutations lead to cancer remain largely unknown. We have demonstrated that a single amino acid change identified in familial disease syndromes, the ETV6 P214L germline mutation, abrogates tumor suppressive function of ETV6 in in vitro and ex vivo models, and have established a mouse model with the ETV6 P214L mutation introduced by CRISPR-Cas9 gene editing. This mouse demonstrates significantly decreased platelet counts, consistent with the thrombocytopenia observed in humans, and may represent an important alternative to the overexpression models of ETV6 germline mutations most studies have relied on to date. We have also employed computational tools to identify factors that may cooperate with ETV6 dysfunction to promote leukemogenesis, and have shown that patients with deletions in ETV6 have an increased frequency of deletions in PAX5. Critically, we have compared primary peripheral blood samples from patients carrying the ETV6 P214L germline variant to matched controls, observing that patients harboring the mutation may have an increased frequency of hematopoietic stem cells mobilized to the peripheral blood. We also probed gene expression in these samples using single-cell RNA sequencing, which revealed that patients and controls do not appear to have different gene expression in their B cell lineages, but do have differential clustering of CD14+ monocytes. Taken together, these data paint a complex picture of ETV6 function in which disruption by a germline mutation may initially produce defects most readily observed in early hematopoietic precursors or myeloid lineage cells, but can then later be converted to a B cell leukemia by additional oncogenic hits. Further investigation of ETV6 biology guided by data from affected patients and utilizing some of the models we have established in this work will continue to move our laboratory toward our overall goal -- novel therapeutic approaches benefitting patients with both acquired and inherited forms of ETV6-associated leukemia.
Notlar:
School code: 1639
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680555.1) | 680555-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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