Malignant Transformation Initiated by Mll-AF9: Gene Dosage and Critical Target Cells

Weili Chen; Ashish R. Kumar; Wendy A. Hudson; Quanzhi Li; Baolin Wu; Rodney A. Staggs; Erik A. Lund; Thien N. Sam; John H. Kersey

doi:10.1016/j.ccr.2008.03.005

Malignant Transformation Initiated by Mll-AF9: Gene Dosage and Critical Target Cells

Weili Chen
, Ashish R. Kumar
, Wendy A. Hudson
, Quanzhi Li
, Baolin Wu
, Rodney A. Staggs
, Erik A. Lund
, Thien N. Sam
, John H. Kersey

Research output: Contribution to journal › Article › peer-review

189 Scopus citations

Abstract

The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin^-Sca1⁺c-kit⁺) stem cells, while committed granulocyte-monocyte progenitors (GMPs) were transformation resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll-AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 upregulated expression of 192 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors.

Original language	English (US)
Pages (from-to)	432-440
Number of pages	9
Journal	Cancer Cell
Volume	13
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2008.03.005
State	Published - May 6 2008

Bibliographical note

Funding Information:
This research was supported by grants from the National Institutes of Health (RO1-CA087053 to J.H.K., and K08-CA122191 to A.R.K.), the Children's Oncology Group and Minnesota Medical Foundation (A.R.K.), and by the Children's Cancer Research Fund (J.H.K. and A.R.K.). The authors thank Scott A. Armstrong and Andrei V. Krivtsov (Children's Hospital/Harvard Medical School) for providing the reagents and protocols for the retroviral studies, discussions of the microarray studies, and reading of the manuscript. Terry Rabbitts (Leeds, UK) originally produced the Mll-AF9 knockin mouse. The University of Minnesota Cancer Center Biostatistical Core (Robin Bliss and Yan Zhang), Flow Cytometry Core (Tucker LeBien), the Histopathology Core (Dr. Gerald O'Sullivan), and the Biomedical Genomics Facility were critical to this project.

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SDG 3 Good Health and Well-being

Keywords

CELLCYCLE

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10.1016/j.ccr.2008.03.005

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title = "Malignant Transformation Initiated by Mll-AF9: Gene Dosage and Critical Target Cells",

abstract = "The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin-Sca1+c-kit+) stem cells, while committed granulocyte-monocyte progenitors (GMPs) were transformation resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll-AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 upregulated expression of 192 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors.",

keywords = "CELLCYCLE",

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note = "Funding Information: This research was supported by grants from the National Institutes of Health (RO1-CA087053 to J.H.K., and K08-CA122191 to A.R.K.), the Children's Oncology Group and Minnesota Medical Foundation (A.R.K.), and by the Children's Cancer Research Fund (J.H.K. and A.R.K.). The authors thank Scott A. Armstrong and Andrei V. Krivtsov (Children's Hospital/Harvard Medical School) for providing the reagents and protocols for the retroviral studies, discussions of the microarray studies, and reading of the manuscript. Terry Rabbitts (Leeds, UK) originally produced the Mll-AF9 knockin mouse. The University of Minnesota Cancer Center Biostatistical Core (Robin Bliss and Yan Zhang), Flow Cytometry Core (Tucker LeBien), the Histopathology Core (Dr. Gerald O'Sullivan), and the Biomedical Genomics Facility were critical to this project. ",

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AU - Wu, Baolin

AU - Staggs, Rodney A.

AU - Lund, Erik A.

AU - Sam, Thien N.

AU - Kersey, John H.

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N2 - The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin-Sca1+c-kit+) stem cells, while committed granulocyte-monocyte progenitors (GMPs) were transformation resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll-AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 upregulated expression of 192 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors.

AB - The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin-Sca1+c-kit+) stem cells, while committed granulocyte-monocyte progenitors (GMPs) were transformation resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll-AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 upregulated expression of 192 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors.

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Malignant Transformation Initiated by Mll-AF9: Gene Dosage and Critical Target Cells

Abstract

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