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

Simple item page
dc.contributor.advisorSamal, Siba Ken_US
dc.contributor.advisorAplan, Peter Den_US
dc.contributor.authorCaudell, David Len_US
dc.contributor.departmentVeterinary Medical Scienceen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2008-10-11T05:52:21Z
dc.date.available2008-10-11T05:52:21Z
dc.date.issued2008-08-08en_US
dc.description.abstractAcute 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.en_US
dc.format.extent17227388 bytes
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/1903/8596
dc.language.isoen_US
dc.subject.pqcontrolledHealth Sciences, Pathologyen_US
dc.subject.pqcontrolledEngineering, Biomedicalen_US
dc.subject.pquncontrolledCALM-AF10en_US
dc.subject.pquncontrolledleukemiaen_US
dc.subject.pquncontrolledhematopoieticen_US
dc.subject.pquncontrolledtranslocationen_US
dc.subject.pquncontrolledtransgenicen_US
dc.subject.pquncontrolledmouseen_US
dc.titleDevelopment of a mouse model for the t(10:11)(p13;q14) chromosomal translocation associated with acute leukemia in humansen_US
dc.typeDissertationen_US

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
umi-umd-5705.pdf
Size:
16.43 MB
Format:
Adobe Portable Document Format
Download

Collections

UMD Theses and Dissertations
Department of Veterinary Medicine Theses and Dissertations