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IPO11 regulates the nuclear import of BZW1/2 and is necessary for AML cells and stem cells.
Nachmias, Boaz; Khan, Dilshad H; Voisin, Veronique; Mer, Arvind S; Thomas, Geethu Emily; Segev, Nadav; St-Germain, Jonathan; Hurren, Rose; Gronda, Marcela; Botham, Aaron; Wang, Xiaoming; Maclean, Neil; Seneviratne, Ayesh K; Duong, Nathan; Xu, Changjiang; Arruda, Andrea; Orouji, Elias; Algouneh, Arash; Hakem, Razqallah; Shlush, Liran; Minden, Mark D; Raught, Brian; Bader, Gary D; Schimmer, Aaron D.
Affiliation
  • Nachmias B; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Khan DH; Department of Hematology, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
  • Voisin V; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Mer AS; Terrence Donnelly Centre for Cellular and Biomedical Research, University of Toronto, Toronto, ON, Canada.
  • Thomas GE; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Segev N; Dept. of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
  • St-Germain J; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Hurren R; Department of Hematology, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
  • Gronda M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Botham A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Wang X; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Maclean N; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Seneviratne AK; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Duong N; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Xu C; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Arruda A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Orouji E; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Algouneh A; Terrence Donnelly Centre for Cellular and Biomedical Research, University of Toronto, Toronto, ON, Canada.
  • Hakem R; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Shlush L; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Minden MD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Raught B; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Bader GD; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Schimmer AD; Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Leukemia ; 36(5): 1283-1295, 2022 05.
Article in En | MEDLINE | ID: mdl-35152270
AML cells are arranged in a hierarchy with stem/progenitor cells giving rise to more differentiated bulk cells. Despite the importance of stem/progenitors in the pathogenesis of AML, the determinants of the AML stem/progenitor state are not fully understood. Through a comparison of genes that are significant for growth and viability of AML cells by way of a CRISPR screen, with genes that are differentially expressed in leukemia stem cells (LSC), we identified importin 11 (IPO11) as a novel target in AML. Importin 11 (IPO11) is a member of the importin ß family of proteins that mediate transport of proteins across the nuclear membrane. In AML, knockdown of IPO11 decreased growth, reduced engraftment potential of LSC, and induced differentiation. Mechanistically, we identified the transcription factors BZW1 and BZW2 as novel cargo of IPO11. We further show that BZW1/2 mediate a transcriptional signature that promotes stemness and survival of LSC. Thus, we demonstrate for the first time how specific cytoplasmic-nuclear regulation supports stem-like transcriptional signature in relapsed AML.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Leukemia, Myeloid, Acute / Beta Karyopherins Type of study: Prognostic_studies Limits: Humans Language: En Journal: Leukemia Year: 2022 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Leukemia, Myeloid, Acute / Beta Karyopherins Type of study: Prognostic_studies Limits: Humans Language: En Journal: Leukemia Year: 2022 Document type: Article