MYC levels govern hematopoietic tumor type and latency in transgenic mice
Deregulated MYC expression has been implicated in the etiology of many human cancers, including hematopoietic malignancies. To explore the impact of widespread constitutive MYC expression in the hematopoietic compartment, we have used a vector containing regulatory elements of the Vav gene to genera...
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Veröffentlicht in: | Blood 2006-07, Vol.108 (2), p.653-661 |
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description | Deregulated MYC expression has been implicated in the etiology of many human cancers, including hematopoietic malignancies. To explore the impact of widespread constitutive MYC expression in the hematopoietic compartment, we have used a vector containing regulatory elements of the Vav gene to generate transgenic mice. VavP-MYC mice are highly tumor-prone and the level of MYC was found to influence both the kinetics and nature of the malignancies that developed. Whereas aggressive T-cell lymphomas rapidly overwhelmed the highest-expressing line, late-onset monocytic tumors greatly predominated in 2 low-expressing lines. These monocytic tumors most likely arise from abnormal macrophage colony-stimulating factor (M-CSF)–dependent progenitor cells having enhanced self-generative capacity. There appears to be a sharp threshold for MYC-induced T-cell lymphomagenesis because merely doubling the MYC level in a low-expressing line by breeding homozygous transgenic animals switched the phenotype from primarily monocytic tumors to exclusively T-cell tumors. Even the low level of MYC, however, clearly affected T-cell cycling, size, and sensitivity to apoptosis, and coexpression of a BCL2 transgene promoted efficient T-cell lymphomagenesis. The implication is that MYC level affects the spontaneous acquisition of synergistic oncogenic mutations. |
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To explore the impact of widespread constitutive MYC expression in the hematopoietic compartment, we have used a vector containing regulatory elements of the Vav gene to generate transgenic mice. VavP-MYC mice are highly tumor-prone and the level of MYC was found to influence both the kinetics and nature of the malignancies that developed. Whereas aggressive T-cell lymphomas rapidly overwhelmed the highest-expressing line, late-onset monocytic tumors greatly predominated in 2 low-expressing lines. These monocytic tumors most likely arise from abnormal macrophage colony-stimulating factor (M-CSF)–dependent progenitor cells having enhanced self-generative capacity. There appears to be a sharp threshold for MYC-induced T-cell lymphomagenesis because merely doubling the MYC level in a low-expressing line by breeding homozygous transgenic animals switched the phenotype from primarily monocytic tumors to exclusively T-cell tumors. Even the low level of MYC, however, clearly affected T-cell cycling, size, and sensitivity to apoptosis, and coexpression of a BCL2 transgene promoted efficient T-cell lymphomagenesis. The implication is that MYC level affects the spontaneous acquisition of synergistic oncogenic mutations.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2006-01-0172</identifier><identifier>PMID: 16537801</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Hematologic Neoplasms - etiology ; Hematologic Neoplasms - genetics ; Hematologic Neoplasms - pathology ; Hematopoietic Stem Cells - pathology ; Humans ; Leukemia, Myeloid - etiology ; Leukemia, Myeloid - pathology ; Lymphoma, T-Cell - etiology ; Lymphoma, T-Cell - pathology ; Macrophage Colony-Stimulating Factor - pharmacology ; Mice ; Mice, Transgenic ; Mutation ; Neoplasia ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins c-bcl-2 ; Proto-Oncogene Proteins c-myc - analysis ; Proto-Oncogene Proteins c-myc - physiology ; Proto-Oncogene Proteins c-vav - genetics ; T-Lymphocytes - pathology</subject><ispartof>Blood, 2006-07, Vol.108 (2), p.653-661</ispartof><rights>2006 American Society of Hematology</rights><rights>Copyright © 2006, The American Society of Hematology 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4342-9290cca4d6c4789f808b112f06c9d64e64065bf63dd9292ce4526aeb43ae824e3</citedby><cites>FETCH-LOGICAL-c4342-9290cca4d6c4789f808b112f06c9d64e64065bf63dd9292ce4526aeb43ae824e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16537801$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Smith, Darrin P.</creatorcontrib><creatorcontrib>Bath, Mary L.</creatorcontrib><creatorcontrib>Metcalf, Donald</creatorcontrib><creatorcontrib>Harris, Alan W.</creatorcontrib><creatorcontrib>Cory, Suzanne</creatorcontrib><title>MYC levels govern hematopoietic tumor type and latency in transgenic mice</title><title>Blood</title><addtitle>Blood</addtitle><description>Deregulated MYC expression has been implicated in the etiology of many human cancers, including hematopoietic malignancies. To explore the impact of widespread constitutive MYC expression in the hematopoietic compartment, we have used a vector containing regulatory elements of the Vav gene to generate transgenic mice. VavP-MYC mice are highly tumor-prone and the level of MYC was found to influence both the kinetics and nature of the malignancies that developed. Whereas aggressive T-cell lymphomas rapidly overwhelmed the highest-expressing line, late-onset monocytic tumors greatly predominated in 2 low-expressing lines. These monocytic tumors most likely arise from abnormal macrophage colony-stimulating factor (M-CSF)–dependent progenitor cells having enhanced self-generative capacity. There appears to be a sharp threshold for MYC-induced T-cell lymphomagenesis because merely doubling the MYC level in a low-expressing line by breeding homozygous transgenic animals switched the phenotype from primarily monocytic tumors to exclusively T-cell tumors. Even the low level of MYC, however, clearly affected T-cell cycling, size, and sensitivity to apoptosis, and coexpression of a BCL2 transgene promoted efficient T-cell lymphomagenesis. The implication is that MYC level affects the spontaneous acquisition of synergistic oncogenic mutations.</description><subject>Animals</subject><subject>Hematologic Neoplasms - etiology</subject><subject>Hematologic Neoplasms - genetics</subject><subject>Hematologic Neoplasms - pathology</subject><subject>Hematopoietic Stem Cells - pathology</subject><subject>Humans</subject><subject>Leukemia, Myeloid - etiology</subject><subject>Leukemia, Myeloid - pathology</subject><subject>Lymphoma, T-Cell - etiology</subject><subject>Lymphoma, T-Cell - pathology</subject><subject>Macrophage Colony-Stimulating Factor - pharmacology</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mutation</subject><subject>Neoplasia</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2</subject><subject>Proto-Oncogene Proteins c-myc - analysis</subject><subject>Proto-Oncogene Proteins c-myc - physiology</subject><subject>Proto-Oncogene Proteins c-vav - genetics</subject><subject>T-Lymphocytes - pathology</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFrGzEQhUVJSJw0f6CHolNu2460WlkLJRBM2wQSckkPPQmtNOso7EqutDb430euTdpcAgM6zDdvRu8R8onBF8YU_9oNMbqKA8gKWKk5_0BmrOGqAuBwRGawa4l2zk7JWc7PAEzUvDkhp0w29VwBm5Hb-98LOuAGh0yXcYMp0CcczRRX0ePkLZ3WY0x02q6QmuDoYCYMdkt9oFMyIS8xFGj0Fj-S494MGS8O7zn59eP74-Kmunv4ebu4vqusqAWvWt6CtUY4acVctb0C1THGe5C2dVKgFCCbrpe1cwXlFkXDpcFO1AYVF1ifk6u97mrdjegshnLIoFfJjyZtdTRev-0E_6TL1zRTbSPapghcHgRS_LPGPOnRZ4vDYALGddZSSWgFrwvI96BNMeeE_esSBnqXgP6bgN4loIHpXQJl6PP_5_0bOVhegG97oFiOG49JZ-uLp-h8QjtpF_17-i-9Q5gv</recordid><startdate>20060715</startdate><enddate>20060715</enddate><creator>Smith, Darrin P.</creator><creator>Bath, Mary L.</creator><creator>Metcalf, Donald</creator><creator>Harris, Alan W.</creator><creator>Cory, Suzanne</creator><general>Elsevier Inc</general><general>The American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20060715</creationdate><title>MYC levels govern hematopoietic tumor type and latency in transgenic mice</title><author>Smith, Darrin P. ; Bath, Mary L. ; Metcalf, Donald ; Harris, Alan W. ; Cory, Suzanne</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4342-9290cca4d6c4789f808b112f06c9d64e64065bf63dd9292ce4526aeb43ae824e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Hematologic Neoplasms - etiology</topic><topic>Hematologic Neoplasms - genetics</topic><topic>Hematologic Neoplasms - pathology</topic><topic>Hematopoietic Stem Cells - pathology</topic><topic>Humans</topic><topic>Leukemia, Myeloid - etiology</topic><topic>Leukemia, Myeloid - pathology</topic><topic>Lymphoma, T-Cell - etiology</topic><topic>Lymphoma, T-Cell - pathology</topic><topic>Macrophage Colony-Stimulating Factor - pharmacology</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mutation</topic><topic>Neoplasia</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins c-bcl-2</topic><topic>Proto-Oncogene Proteins c-myc - analysis</topic><topic>Proto-Oncogene Proteins c-myc - physiology</topic><topic>Proto-Oncogene Proteins c-vav - genetics</topic><topic>T-Lymphocytes - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Smith, Darrin P.</creatorcontrib><creatorcontrib>Bath, Mary L.</creatorcontrib><creatorcontrib>Metcalf, Donald</creatorcontrib><creatorcontrib>Harris, Alan W.</creatorcontrib><creatorcontrib>Cory, Suzanne</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smith, Darrin P.</au><au>Bath, Mary L.</au><au>Metcalf, Donald</au><au>Harris, Alan W.</au><au>Cory, Suzanne</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MYC levels govern hematopoietic tumor type and latency in transgenic mice</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2006-07-15</date><risdate>2006</risdate><volume>108</volume><issue>2</issue><spage>653</spage><epage>661</epage><pages>653-661</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Deregulated MYC expression has been implicated in the etiology of many human cancers, including hematopoietic malignancies. To explore the impact of widespread constitutive MYC expression in the hematopoietic compartment, we have used a vector containing regulatory elements of the Vav gene to generate transgenic mice. VavP-MYC mice are highly tumor-prone and the level of MYC was found to influence both the kinetics and nature of the malignancies that developed. Whereas aggressive T-cell lymphomas rapidly overwhelmed the highest-expressing line, late-onset monocytic tumors greatly predominated in 2 low-expressing lines. These monocytic tumors most likely arise from abnormal macrophage colony-stimulating factor (M-CSF)–dependent progenitor cells having enhanced self-generative capacity. There appears to be a sharp threshold for MYC-induced T-cell lymphomagenesis because merely doubling the MYC level in a low-expressing line by breeding homozygous transgenic animals switched the phenotype from primarily monocytic tumors to exclusively T-cell tumors. Even the low level of MYC, however, clearly affected T-cell cycling, size, and sensitivity to apoptosis, and coexpression of a BCL2 transgene promoted efficient T-cell lymphomagenesis. The implication is that MYC level affects the spontaneous acquisition of synergistic oncogenic mutations.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>16537801</pmid><doi>10.1182/blood-2006-01-0172</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Hematologic Neoplasms - etiology Hematologic Neoplasms - genetics Hematologic Neoplasms - pathology Hematopoietic Stem Cells - pathology Humans Leukemia, Myeloid - etiology Leukemia, Myeloid - pathology Lymphoma, T-Cell - etiology Lymphoma, T-Cell - pathology Macrophage Colony-Stimulating Factor - pharmacology Mice Mice, Transgenic Mutation Neoplasia Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins c-bcl-2 Proto-Oncogene Proteins c-myc - analysis Proto-Oncogene Proteins c-myc - physiology Proto-Oncogene Proteins c-vav - genetics T-Lymphocytes - pathology |
title | MYC levels govern hematopoietic tumor type and latency in transgenic mice |
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