TY - JOUR
T1 - IPO11 regulates the nuclear import of BZW1/2 and is necessary for AML cells and stem cells
AU - Nachmias, Boaz
AU - Khan, Dilshad H
AU - Voisin, Veronique
AU - Mer, Arvind S
AU - Thomas, Geethu Emily
AU - Segev, Nadav
AU - St-Germain, Jonathan
AU - Hurren, Rose
AU - Gronda, Marcela
AU - Botham, Aaron
AU - Wang, Xiaoming
AU - Maclean, Neil
AU - Seneviratne, Ayesh K
AU - Duong, Nathan
AU - Xu, Changjiang
AU - Arruda, Andrea
AU - Orouji, Elias
AU - Algouneh, Arash
AU - Hakem, Razqallah
AU - Shlush, Liran
AU - Minden, Mark D
AU - Raught, Brian
AU - Bader, Gary D
AU - Schimmer, Aaron D
N1 - Publisher Copyright: © 2022, The Author(s).
PY - 2022/5
Y1 - 2022/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85124658947&partnerID=8YFLogxK
U2 - 10.1038/s41375-022-01513-4
DO - 10.1038/s41375-022-01513-4
M3 - مقالة
C2 - 35152270
SN - 0887-6924
VL - 36
SP - 1283
EP - 1295
JO - Leukemia
JF - Leukemia
IS - 5
ER -