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.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by the dysregulated proliferation and differentiation arrest, resulting in the accumulation of immature myeloid progenitors in the bone marrow and peripheral blood
importin 11 (IPO11) is a critical target in leukemic stem cells To identify genes that are essential for the viability of LSC, we overlaid the results of our previously performed, genome-wide CRISPR screen [5] with the expression of genes enriched in functionally defined LSCs [18]
Three hits from our CRISPR screen were expressed at higher levels in the LSC+ fraction compared to IPO11: RPAP2, KDSR, and CDK6
Summary
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by the dysregulated proliferation and differentiation arrest, resulting in the accumulation of immature myeloid progenitors in the bone marrow and peripheral blood. While most patients achieve remission with initial therapy, the majority relapse leading to poor overall survival [1]. Relapse is frequently driven by a rare subset of leukemic stem cells (LSC) [2, 3]. LSC maintain stem-like transcriptional signatures with selfrenewal ability, specific metabolic features [4, 5] and resistance to chemotherapy [6]. Understanding the biological mechanisms that maintain LSC should help to identify new therapeutic strategies for this disease. We report the identification of IPO11, a regulator of protein trafficking between the nucleus and cytoplasm, as a mediator of stemness in LSC
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