IPO11 regulates the nuclear import of BZW1/2 and is necessary for AML cells and stem cells

Boaz Nachmias, Dilshad H Khan, Veronique Voisin, Arvind S Mer, Geethu Emily Thomas, Nadav Segev, Jonathan St-Germain, Rose Hurren, Marcela Gronda, Aaron Botham, Xiaoming Wang, Neil Maclean, Ayesh K Seneviratne, Nathan Duong, Changjiang Xu, Andrea Arruda, Elias Orouji, Arash Algouneh, Razqallah Hakem, Liran ShlushMark D Minden, Brian Raught, Gary D Bader, Aaron D Schimmer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

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 β 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.
Original languageEnglish
Pages (from-to)1283-1295
Number of pages13
JournalLeukemia
Volume36
Issue number5
DOIs
Publication statusPublished - May 2022

Funding

Funding Information: We thank Jill Flewelling (Princess Margaret Cancer Centre) for administrative assistance and the Leukemia Tissue Bank (Princess Margaret Cancer Centre) for providing the primary AML samples. This work was supported by the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research with funding provided by the Ontario Ministry of Research and Innovation, the Princess Margaret Cancer Centre Foundation, and the Ministry of Long-Term Health and Planning in the Province of Ontario. ADS holds the Ronald N. Buick Chair in Oncology Research. BN research is supported by the Israel Cancer Association Grant for outstanding research on behalf of G. Doron and the Israel Science Foundation physician-scientist Grant. Funding Information: We thank Jill Flewelling (Princess Margaret Cancer Centre) for administrative assistance and the Leukemia Tissue Bank (Princess Margaret Cancer Centre) for providing the primary AML samples. This work was supported by the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research with funding provided by the Ontario Ministry of Research and Innovation, the Princess Margaret Cancer Centre Foundation, and the Ministry of Long-Term Health and Planning in the Province of Ontario. ADS holds the Ronald N. Buick Chair in Oncology Research. BN research is supported by the Israel Cancer Association Grant for outstanding research on behalf of G. Doron and the Israel Science Foundation physician-scientist Grant. Funding Information: ADS has received research funding from Takeda Pharmaceuticals and Medivir AB, and consulting fees/honorarium from Takeda, BMS, Novartis, Jazz, and Otsuka Pharmaceuticals. ADS is named on a patent application for the use of DNT cells to treat AML. Publisher Copyright: © 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

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