ZFX Controls Propagation and Prevents Differentiation of Acute T-Lymphoblastic and Myeloid Leukemia

• Published in: Cell reports (Cambridge) 2014-02, Vol.6 (3), p.528-540
• Main Authors: Weisberg, Stuart P., Smith-Raska, Matthew R., Esquilin, Jose M., Zhang, Ji, Arenzana, Teresita L., Lau, Colleen M., Churchill, Michael, Pan, Haiyan, Klinakis, Apostolos, Dixon, Jack E., Mirny, Leonid A., Mukherjee, Siddhartha, Reizis, Boris
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic - pathology; Clone Cells; Gene Expression Regulation, Leukemic; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Mice; Mitochondria - enzymology; Phenotype; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proto-Oncogene Proteins c-myc - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Receptors, Notch - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.01.007

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. [Display omitted] •Zfx is important for the initiation and propagation of AML and T-ALL•Loss of Zfx causes differentiation in both leukemia types•Zfx facilitates leukemic transformation and gene induction by Myc•Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2 Two major types of acute leukemia, T-lymphoblastic (T-ALL) and myeloid (AML), originate from different lineages through distinct oncogenic events. Common mechanisms that maintain the growth and immature phenotype of leukemia-propagating cells in T-ALL and AML are poorly characterized. Reizis and colleagues now show that transcription factor Zfx facilitates propagation and blocks differentiation in both leukemia types. These studies reveal an endogenous regulator that is hijacked by disparate leukemia types to facilitate their propagation.