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Development of a mouse model for the...

University of Maryland, College Park., Veterinary Medical Science.

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Development of a mouse model for the t(10:11)(p13;q14) chromosomal translocation associated with acute leukemia in humans.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Development of a mouse model for the t(10:11)(p13;q14) chromosomal translocation associated with acute leukemia in humans./
Author:	Caudell, David L.
Description:	190 p.
Notes:	Advisers: Siba K. Samal; Peter D. Aplan.
Contained By:	Dissertation Abstracts International69-08B.
Subject:	Engineering, Biomedical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3324915
ISBN:	9780549781707

Development of a mouse model for the t(10:11)(p13;q14) chromosomal translocation associated with acute leukemia in humans.
Caudell, David L.

Development of a mouse model for the t(10:11)(p13;q14) chromosomal translocation associated with acute leukemia in humans. - 190 p.

Advisers: Siba K. Samal; Peter D. Aplan.

Thesis (Ph.D.)--University of Maryland, College Park, 2008.

Acute leukemia is associated with a wide spectrum of gross chromosomal rearrangements. These acquired mutations include balanced and unbalanced chromosomal translocations. The analysis of chromosomal translocations has provided much insight into understanding the biology of hematologic malignancies, leading to improved diagnosis and classification, as well as identification of novel therapeutic targets. The rare but recurring chromosomal translocation [t(10;11)(p13;q21)] results in a CALM-AF10 fusion that occurs in patients with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). CALM-AF10 transgenic mice developed AML with lymphoid features and had Hoxa gene cluster upregulation. In this model, mice developed leukemia after a long latency period with incomplete penetrance. These findings suggest that additional genetic events are needed to complement CALM-AF10 mediated leukemic transformation. Retroviral insertional mutagenesis was used to identify complementary genetic events that might collaborate with CALM-AF10 during leukemic transformation. A cohort of CALM-AF10 mice was infected with the Mol4070LTR retrovirus; by 5.5 months of age, 50% of the transgenic mice developed AML, a clear acceleration of disease onset compared to either wild type littermates injected with the retrovirus or CALM-AF10 mice not injected with the retrovirus. The tumors assayed by Southern blotting for viral integration showed clonal to oligoclonal expansion. Ligation-mediated PCR and sequence analysis of DNA derived from leukemic cells was used to identify potential collaborating genes at the retroviral insertion sites including Evi1, Nf1, kRas, Zeb2, and Mnl. Identification of these genes as a potential collaborating gene with CALM-AF10 supports the emerging paradigm in leukemia biology that predicts that most, if not all leukemic cells must undergo at least two collaborative events to produce a fully transformed cell. One of these events typically leads to impaired differentiation and enhanced renewal of stem cells, whereas the second event leads to increased proliferation and/or decreased apoptosis. It has been shown here that retroviral infection accelerates the onset of acute leukemia, and identified genes that potentially collaborate with the CALM-AF10 fusion gene in the leukemic transformation process. This transgenic murine model serves as a model system for studying leukemogenesis similar to that observed in humans with leukemia.

ISBN: 9780549781707Subjects--Topical Terms:

1017684
Engineering, Biomedical.

Development of a mouse model for the t(10:11)(p13;q14) chromosomal translocation associated with acute leukemia in humans.
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100 1 $a Caudell, David L. $3 1057383
245 1 0 $a Development of a mouse model for the t(10:11)(p13;q14) chromosomal translocation associated with acute leukemia in humans.
300 $a 190 p.
500 $a Advisers: Siba K. Samal; Peter D. Aplan.
500 $a Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4685.
502 $a Thesis (Ph.D.)--University of Maryland, College Park, 2008.
520 $a Acute leukemia is associated with a wide spectrum of gross chromosomal rearrangements. These acquired mutations include balanced and unbalanced chromosomal translocations. The analysis of chromosomal translocations has provided much insight into understanding the biology of hematologic malignancies, leading to improved diagnosis and classification, as well as identification of novel therapeutic targets. The rare but recurring chromosomal translocation [t(10;11)(p13;q21)] results in a CALM-AF10 fusion that occurs in patients with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). CALM-AF10 transgenic mice developed AML with lymphoid features and had Hoxa gene cluster upregulation. In this model, mice developed leukemia after a long latency period with incomplete penetrance. These findings suggest that additional genetic events are needed to complement CALM-AF10 mediated leukemic transformation. Retroviral insertional mutagenesis was used to identify complementary genetic events that might collaborate with CALM-AF10 during leukemic transformation. A cohort of CALM-AF10 mice was infected with the Mol4070LTR retrovirus; by 5.5 months of age, 50% of the transgenic mice developed AML, a clear acceleration of disease onset compared to either wild type littermates injected with the retrovirus or CALM-AF10 mice not injected with the retrovirus. The tumors assayed by Southern blotting for viral integration showed clonal to oligoclonal expansion. Ligation-mediated PCR and sequence analysis of DNA derived from leukemic cells was used to identify potential collaborating genes at the retroviral insertion sites including Evi1, Nf1, kRas, Zeb2, and Mnl. Identification of these genes as a potential collaborating gene with CALM-AF10 supports the emerging paradigm in leukemia biology that predicts that most, if not all leukemic cells must undergo at least two collaborative events to produce a fully transformed cell. One of these events typically leads to impaired differentiation and enhanced renewal of stem cells, whereas the second event leads to increased proliferation and/or decreased apoptosis. It has been shown here that retroviral infection accelerates the onset of acute leukemia, and identified genes that potentially collaborate with the CALM-AF10 fusion gene in the leukemic transformation process. This transgenic murine model serves as a model system for studying leukemogenesis similar to that observed in humans with leukemia.
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773 0 $t Dissertation Abstracts International $g 69-08B.
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