Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia.
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.
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Junping
J
Wei
Mark
M
Wunderlich
Catherine
C
Fox
Sara
S
Alvarez
Juan C
JC
Cigudosa
Jamie S
JS
Wilhelm
Yi
Y
Zheng
Jose A
JA
Cancelas
Yi
Y
Gu
Michael
M
Jansen
Jorge F
JF
Dimartino
James C
JC
Mulloy
D000782:Aneuploidy; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D019070:Cell Lineage; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002880:Chromosomes, Human, Pair 11; D004777:Environment; D005312:Fetal Blood / Q000276:immunology / Q000378:metabolism; D053686:Fetal Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007942:Leukemia, Experimental / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D039902:Multipotent Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D013045:Species Specificity; D033581:Stem Cell Transplantation; D013997:Time Factors; D014161:Transduction, Genetic; D014178:Translocation, Genetic; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D018952:Antigens, CD34; D036341:Intercellular Signaling Peptides and Proteins; C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D020744:rac GTP-Binding Proteins