ALL1 fusion proteins induce deregulation of EphA7 and ERK phosphorylation in human acute leukemias.

Abstract

Erythropoietin-producing hepatoma-amplified sequence (Eph) receptor tyrosine kinases and their cell-surface-bound ligands, the ephrins, function as a unique signaling system triggered by cell-to-cell interaction and have been shown to mediate neurodevelopmental processes. In addition, recent studies showed deregulation of some of Eph/ephrin genes in human malignancies, suggesting the involvement of this signaling pathway in tumorigenesis. The ALL1 (also termed MLL) gene on human chromosome 11q23 was isolated by virtue of its involvement in recurrent chromosome translocations associated with acute leukemias with poor prognosis. The translocations fuse ALL1 to any of >50 partner genes and result in production of chimeric proteins composed of the ALL1 N terminus and the C terminus of the partner protein. The most common translocations in ALL1-associated leukemias are t(4;11) and t(9;11), which generate ALL1/AF4 and ALL1/AF9 fusion protein, respectively. In the present study, we sought to determine whether ALL1 fusion proteins are involved in regulation of Eph/ephrin genes. Screening of K562 cells producing recombinant ALL1/AF4 or ALL1/AF9 fusion protein revealed transcriptional up-regulation of the EphA7. Consistent with this finding, siRNA-mediated suppression of ALL1/AF4 in SEMK2 cells carrying the t(4;11) chromosome translocation resulted in down-regulation of EphA7. ChIP analysis demonstrated the occupancy of tagged ALL1 fusion proteins on the EphA7 promoter, pointing to EphA7 as a direct target of the formers. Further studies demonstrate that EphA7 up-regulation is accompanied by ERK phosphorylation. Finally, we show apoptotic cell death, specific for leukemic cells carrying the t(4;11) chromosome translocation, after treatment of the cells with an ERK phosphorylation blocker.

• Authors: Hiroshi Nakanishi, Tatsuya Nakamura, Eli Canaani, Carlo M Croce
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 36 Pg. 14442-7 (Sep 04 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17726105 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• KMT2A protein, human
• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• Myeloid-Lymphoid Leukemia Protein
• 5-iodotubercidin
• Histone-Lysine N-Methyltransferase
• Receptor, EphA7
• Extracellular Signal-Regulated MAP Kinases
• Tubercidin

Topics

• Acute Disease
• Apoptosis (drug effects)
• Cell Line, Tumor
• Chromosomes, Human, Pair 4 (genetics)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Gene Expression Regulation, Neoplastic
• Genome, Human (genetics)
• Histone-Lysine N-Methyltransferase
• Humans
• Leukemia (genetics, metabolism, pathology)
• Myeloid-Lymphoid Leukemia Protein (genetics, metabolism)
• Oncogene Proteins, Fusion (genetics, metabolism)
• Phosphorylation (drug effects)
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• Receptor, EphA7 (metabolism)
• Transcription, Genetic (genetics)
• Tubercidin (analogs & derivatives, pharmacology)