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PMID: 18538732 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia.

Cancer cell ·Vol. 13 ·No. 6 ·2008-06-00 ·Pages 483-95

Wei J, Wunderlich M, Fox C, Alvarez S, Cigudosa JC, Wilhelm JS, Zheng Y, Cancelas JA, Gu Y, Jansen M, Dimartino JF, Mulloy JC

Abstract

Faithful modeling of mixed-lineage leukemia in murine cells has been difficult to achieve. We show that expression of MLL-AF9 in human CD34+ cells induces acute myeloid, lymphoid, or mixed-lineage leukemia in immunodeficient mice. Some leukemia stem cells (LSC) were multipotent and could be lineage directed by altering either the growth factors or the recipient strain of mouse, highlighting the importance of microenvironmental cues. Other LSC were strictly lineage committed, demonstrating the heterogeneity of the stem cell compartment in MLL disease. Targeting the Rac signaling pathway by pharmacologic or genetic means resulted in rapid and specific apoptosis of MLL-AF9 cells, suggesting that the Rac signaling pathway may be a valid therapeutic target in MLL-rearranged AML.

MeSH Terms
Aneuploidy Animals Antigens, CD34/analysis Apoptosis Cell Culture Techniques Cell Line, Transformed Cell Lineage Cell Proliferation Cell Transformation, Neoplastic/genetics,metabolism,pathology Chromosomes, Human, Pair 11 Environment Fetal Blood/immunology,metabolism Fetal Stem Cells/immunology,metabolism,pathology Gene Expression Profiling Gene Expression Regulation, Neoplastic Genotype Humans Intercellular Signaling Peptides and Proteins/metabolism Leukemia, Experimental/metabolism,pathology Leukemia, Myeloid, Acute/genetics,metabolism,pathology Mice Mice, Inbred NOD Mice, SCID Multipotent Stem Cells/immunology,metabolism,pathology Myeloid-Lymphoid Leukemia Protein/genetics,metabolism Neoplastic Stem Cells/immunology,metabolism,pathology Oncogene Proteins, Fusion/genetics,metabolism Phenotype Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics,metabolism,pathology Signal Transduction Species Specificity Stem Cell Transplantation Time Factors Transduction, Genetic Translocation, Genetic rac GTP-Binding Proteins/genetics,metabolism
Chemicals
Antigens, CD34 Intercellular Signaling Peptides and Proteins MLL-AF9 fusion protein, human Oncogene Proteins, Fusion Myeloid-Lymphoid Leukemia Protein rac GTP-Binding Proteins
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Wei Junping
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Wunderlich Mark
Fox Catherine
Alvarez Sara
Cigudosa Juan C
Wilhelm Jamie S
Zheng Yi
Cancelas Jose A
Gu Yi
Jansen Michael
Dimartino Jorge F
Mulloy James C
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2008.04.020
Published
2008-06-00
Pages
483-95
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2486365
Subset
IM
Grants
NCI NIH HHS · R01 CA118319 · United States
NCI NIH HHS · K01 CA090370 · United States
NCRR NIH HHS · M01 RR 08084 · United States
NCI NIH HHS · R01 CA118319-01 · United States
NCRR NIH HHS · M01 RR008084 · United States
NCI NIH HHS · CA118319 · United States
NCI NIH HHS · K01 CA090370-06 · United States
NCI NIH HHS · CA90370 · United States
Databases
GEO
GSE7011
Corrections
CommentIn
PMID: 18538728
External Links
PubMed source DOI: 10.1016/j.ccr.2008.04.020 PMC Full Text View journal details
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