ZFX controls propagation and prevents differentiation of acute T-lymphoblastic and myeloid leukemia.
Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator.
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
Stuart P
SP
Weisberg
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
Matthew R
MR
Smith-Raska
Division of Pediatric Hematology, Columbia University Medical Center, New York, NY 10032, USA.
Jose M
JM
Esquilin
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
Ji
J
Zhang
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
Teresita L
TL
Arenzana
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
Colleen M
CM
Lau
Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center, New York, NY 10032, USA.
Michael
M
Churchill
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
Haiyan
H
Pan
Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
Apostolos
A
Klinakis
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
Jack E
JE
Dixon
Institute for Medical Engineering and Science and Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Leonid A
LA
Mirny
Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center, New York, NY 10032, USA.
Siddhartha
S
Mukherjee
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: bvr2101@columbia.edu.
Boris
B
Reizis
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002999:Clone Cells; D015973:Gene Expression Regulation, Leukemic; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases
D007521:Isocitrate Dehydrogenase; D051741:Kruppel-Like Transcription Factors; D051059:PTEN Phosphohydrolase; D016271:Proto-Oncogene Proteins c-myc; D051880:Receptors, Notch; C062076:zinc finger protein, X-linked; C492433:Ptpmt1 protein, mouse; D017027:Protein Tyrosine Phosphatases