| Autor: |
Kaufmann, Kerstin B., Garcia-Prat, Laura, Liu, Qiang, Ng, Stanley W.K., Takayanagi, Shin-Ichiro, Mitchell, Amanda, Wienholds, Erno, van Galen, Peter, Cumbaa, Christian A., Tsay, Mike J., Pastrello, Chiara, Wagenblast, Elvin, Krivdova, Gabriela, Minden, Mark D., Lechman, Eric R., Zandi, Sasan, Jurisica, Igor, Wang, Jean C.Y., Xie, Stephanie Z., Dick, John E. |
| Zdroj: |
Blood; May 2019, Vol. 133 Issue: 20 p2198-2211, 14p |
| Abstrakt: |
There is a growing body of evidence that the molecular properties of leukemia stem cells (LSCs) are associated with clinical outcomes in acute myeloid leukemia (AML), and LSCs have been linked to therapy failure and relapse. Thus, a better understanding of the molecular mechanisms that contribute to the persistence and regenerative potential of LSCs is expected to result in the development of more effective therapies. We therefore interrogated functionally validated data sets of LSC-specific genes together with their known protein interactors and selected 64 candidates for a competitive in vivo gain-of-function screen to identify genes that enhanced stemness in human cord blood hematopoietic stem and progenitor cells. A consistent effect observed for the top hits was the ability to restrain early repopulation kinetics while preserving regenerative potential. Overexpression (OE) of the most promising candidate, the orphan gene C3orf54/INKA1, in a patient-derived AML model (8227) promoted the retention of LSCs in a primitive state manifested by relative expansion of CD34+cells, accumulation of cells in G0, and reduced output of differentiated progeny. Despite delayed early repopulation, at later times, INKA1-OE resulted in the expansion of self-renewing LSCs. In contrast, INKA1silencing in primary AML reduced regenerative potential. Mechanistically, our multidimensional confocal analysis found that INKA1regulates G0exit by interfering with nuclear localization of its target PAK4, with concomitant reduction of global H4K16ac levels. These data identify INKA1as a novel regulator of LSC latency and reveal a link between the regulation of stem cell kinetics and pool size during regeneration. |
| Databáze: |
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