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Study of the Role of USP22 (Ubiquiti...

Melo-Cardenas, Sindey Johanna.

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Study of the Role of USP22 (Ubiquitin Specific Peptidase 22) in Hematopoiesis and Kras-induced Myeloproliferative Neoplasm.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Study of the Role of USP22 (Ubiquitin Specific Peptidase 22) in Hematopoiesis and Kras-induced Myeloproliferative Neoplasm./
作者:	Melo-Cardenas, Sindey Johanna.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	105 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-05, Section: B.
Contained By:	Dissertations Abstracts International80-05B.
標題:	Medicine. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10844362
ISBN:	9780438551398

Study of the Role of USP22 (Ubiquitin Specific Peptidase 22) in Hematopoiesis and Kras-induced Myeloproliferative Neoplasm.
Melo-Cardenas, Sindey Johanna.

Study of the Role of USP22 (Ubiquitin Specific Peptidase 22) in Hematopoiesis and Kras-induced Myeloproliferative Neoplasm. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 105 p.

Source: Dissertations Abstracts International, Volume: 80-05, Section: B.

Thesis (Ph.D.)--Northwestern University, 2018.

This item must not be added to any third party search indexes.

The deubiquitylase USP22 (Ubiquitin Specific Peptidase 22) has been associated with cancer development, metastasis and chemotherapy resistance in different types of cancer including hematological malignances. USP22 is highly expressed in myeloid and lymphoid leukemias. Furthermore, human acute myeloid leukemia (AML) samples with mutations in an upstream activator of Ras signaling showed higher expression of USP22. Despite the above-mentioned evidence relating the role of USP22 in hematological malignances, the function of USP22 in normal blood cell development or leukemogenesis is unknown. USP22 belongs to the transcriptional complex SAGA (Spt- Ada-Gcn5-Acetyltransferase) that is involved in histone modification, regulation of the transcriptional machinery, gene expression co-activation and mRNA export. Although most of what is known about USP22 has been described in yeast, a few studies in mammalian cells have shown that USP22 removes ubiquitin chains from different substrates including Histone 2A and 2B. It is required for the transition from self-renewal to differentiation in embryonic stem cells, for the transcription of Myc target genes, the progression of the cell cycle and its germ line deletion in mice is lethal. We aimed to investigate the function of USP22 during adult hematopoiesis and in a model of Ras-driven myeloproliferative neoplasm (MPN) by using a genetic mouse model of USP22 for the first time. Our results showed that under normal steady-state hematopoiesis USP22 was necessary for B-lymphopoiesis but was dispensable for myelopoiesis. The molecular mechanisms involved the deubiquitylation of H2Aub at E2A target genes. In the Ras-driven MPN model, we found a novel tumor suppressor role for USP22. USP22 deficiency in Ras-driven MPN mice resulted in shorter survival compared to control mice. This was due to a block in myeloid cell differentiation leading to the generation of a more aggressive type of leukemia. The molecular mechanisms involved USP22 positive regulation of PU.1 protein expression. Overall, our findings uncovered unexpected roles for USP22 in hematopoiesis and Ras-induced leukemogenesis and provide further insights into the function of USP22 in vivo.

ISBN: 9780438551398Subjects--Topical Terms:

641104
Medicine.

Study of the Role of USP22 (Ubiquitin Specific Peptidase 22) in Hematopoiesis and Kras-induced Myeloproliferative Neoplasm.
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520 $a The deubiquitylase USP22 (Ubiquitin Specific Peptidase 22) has been associated with cancer development, metastasis and chemotherapy resistance in different types of cancer including hematological malignances. USP22 is highly expressed in myeloid and lymphoid leukemias. Furthermore, human acute myeloid leukemia (AML) samples with mutations in an upstream activator of Ras signaling showed higher expression of USP22. Despite the above-mentioned evidence relating the role of USP22 in hematological malignances, the function of USP22 in normal blood cell development or leukemogenesis is unknown. USP22 belongs to the transcriptional complex SAGA (Spt- Ada-Gcn5-Acetyltransferase) that is involved in histone modification, regulation of the transcriptional machinery, gene expression co-activation and mRNA export. Although most of what is known about USP22 has been described in yeast, a few studies in mammalian cells have shown that USP22 removes ubiquitin chains from different substrates including Histone 2A and 2B. It is required for the transition from self-renewal to differentiation in embryonic stem cells, for the transcription of Myc target genes, the progression of the cell cycle and its germ line deletion in mice is lethal. We aimed to investigate the function of USP22 during adult hematopoiesis and in a model of Ras-driven myeloproliferative neoplasm (MPN) by using a genetic mouse model of USP22 for the first time. Our results showed that under normal steady-state hematopoiesis USP22 was necessary for B-lymphopoiesis but was dispensable for myelopoiesis. The molecular mechanisms involved the deubiquitylation of H2Aub at E2A target genes. In the Ras-driven MPN model, we found a novel tumor suppressor role for USP22. USP22 deficiency in Ras-driven MPN mice resulted in shorter survival compared to control mice. This was due to a block in myeloid cell differentiation leading to the generation of a more aggressive type of leukemia. The molecular mechanisms involved USP22 positive regulation of PU.1 protein expression. Overall, our findings uncovered unexpected roles for USP22 in hematopoiesis and Ras-induced leukemogenesis and provide further insights into the function of USP22 in vivo.
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