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Cell Rep. 2014 Feb 13;6(3):528-40. doi: 10.1016/j.celrep.2014.01.007. Epub 2014 Jan 30.

ZFX controls propagation and prevents differentiation of acute T-lymphoblastic and myeloid leukemia.

Author information

1
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
2
Division of Pediatric Hematology, Columbia University Medical Center, New York, NY 10032, USA.
3
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
4
Department of Medicine, Division of Hematology/Oncology, Columbia University Medical Center, New York, NY 10032, USA.
5
Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
6
Institute for Medical Engineering and Science and Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: bvr2101@columbia.edu.

Abstract

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.

PMID:
24485662
PMCID:
PMC3936793
DOI:
10.1016/j.celrep.2014.01.007
[Indexed for MEDLINE]
Free PMC Article
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