A CALM-derived nuclear export signal is essential for CALM-AF10–mediated leukemogenesis

Wechsler, Daniel S. ; Scotland, Paula ; et al.

In: Blood, Jg. 121 (2013-06-06), S. 4758-4768

Online unknown

Zugriff:

The t(10;11) chromosomal translocation gives rise to the CALM-AF10 fusion gene and is found in patients with aggressive and difficult-to-treat hematopoietic malignancies. CALM-AF10-driven leukemias are characterized by HOXA gene up-regulation and a global reduction in H3K79 methylation. DOT1L, the H3K79 methyltransferase, interacts with the octapeptide/leucine zipper domain of AF10, and this region has been shown to be necessary and sufficient for CALM-AF10-mediated transformation. However, the precise role of CALM in leukemogenesis remains unclear. Here, we show that CALM contains a nuclear export signal (NES) that mediates cytoplasmic localization of CALM-AF10 and is necessary for CALM-AF10-dependent transformation. Fusions of the CALM NES (NES(CALM)-AF10) or NES motifs from heterologous proteins (ABL1, Rev, PKIA, APC) in-frame with AF10 are sufficient to immortalize murine hematopoietic progenitors in vitro. The CALM NES is essential for CALM-AF10-dependent Hoxa gene up-regulation and aberrant H3K79 methylation, possibly by mislocalization of DOT1L. Finally, we observed that CALM-AF10 leukemia cells are selectively sensitive to inhibition of nuclear export by Leptomycin B. These findings uncover a novel mechanism of leukemogenesis mediated by the nuclear export pathway and support further investigation of the utility of nuclear export inhibitors as therapeutic agents for patients with CALM-AF10 leukemias.

Titel:	A CALM-derived nuclear export signal is essential for CALM-AF10–mediated leukemogenesis
Autor/in / Beteiligte Person:	Wechsler, Daniel S. ; Scotland, Paula ; Conway, Amanda E. ; Lavau, Catherine
Link:	View record at OpenAIRE (Volltext) https://doi.org/10.1182/blood-2012-06-435792
Zeitschrift:	Blood, Jg. 121 (2013-06-06), S. 4758-4768
Veröffentlichung:	American Society of Hematology, 2013
Medientyp:	unknown
ISSN:	1528-0020 (print) ; 0006-4971 (print)
DOI:	10.1182/blood-2012-06-435792
Schlagwort:	Leucine zipper Oncogene Proteins, Fusion Molecular Sequence Data Immunology Active Transport, Cell Nucleus Chromosomal translocation Biology Biochemistry Fusion gene Mice chemistry.chemical_compound Animals Humans Amino Acid Sequence Nuclear export signal Cells, Cultured Bone Marrow Transplantation Homeodomain Proteins Nuclear Export Signals Myeloid Neoplasia Antibiotics, Antineoplastic Leukemia, Experimental ABL Sequence Homology, Amino Acid Cell Biology Hematology DOT1L Leptomycin Methylation Flow Cytometry Hematopoietic Stem Cells Molecular biology Cell biology Mice, Inbred C57BL Survival Rate Protein Transport Cell Transformation, Neoplastic Gene Expression Regulation chemistry Monomeric Clathrin Assembly Proteins Fatty Acids, Unsaturated
Sonstiges:	Nachgewiesen in: OpenAIRE Rights: OPEN

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