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

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

in Acute myeloid leukemia / Cell differentiation / CRISPR / Gene regulation / Genes / Leukemia / Nuclear transport / Pathogenesis / Progenitor cells / Protein transport / Proteins / Stem cells / Transcription factors

2022

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

2022

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2022

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Journal Article

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

Algouneh Arash,

Maclean, Neil,

Bader, Gary D,

Hakem Razqallah,

Voisin Veronique,

Minden, Mark D,

Khan, Dilshad H,

St-Germain, Jonathan,

Hurren Rose,

Arruda, Andrea,

Orouji Elias,

Raught, Brian,

Botham, Aaron,

Schimmer, Aaron D,

Mer, Arvind S,

Thomas Geethu Emily,

Gronda Marcela,

Seneviratne, Ayesh K,

Xu, Changjiang,

Shlush Liran,

Nachmias Boaz,

Wang, Xiaoming,

Segev Nadav,

Duong, Nathan

2022

Overview

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.

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Publisher

Nature Publishing Group

Subject

Acute myeloid leukemia

/ Cell differentiation

/ CRISPR

/ Gene regulation

/ Genes

/ Leukemia

/ Nuclear transport