Abstract
LIS1 prevents HSC and leukemic differentiation by promoting symmetric cell division.
Major finding: LIS1 prevents HSC and leukemic differentiation by promoting symmetric cell division.
Mechanism: LIS1-mediated spindle positioning regulates daughter cell inheritance of fate determinants.
Impact: Regulators of symmetric cell division maintain the undifferentiated state of HSCs and leukemic cells.
The characteristics of daughter cells after cell division are largely regulated by the polarized distribution and inheritance of cell fate determinants, which is required to maintain the balance between immature and differentiated cell populations. Hematopoietic stem cells (HSC) undergo both symmetric and asymmetric division, prompting Zimdahl and colleagues to investigate the molecular mechanisms that govern fate determinant inheritance in HSCs and assess whether deregulation of this process affects stem cell maintenance and tumorigenesis. Focusing on the dynein-binding protein LIS1, which regulates cell division symmetry by determining mitotic spindle orientation, the authors showed that Lis1 is required to maintain murine embryonic and adult HSC function in a cell-autonomous manner. Gene expression analysis of Lis1-deficient HSCs revealed a decrease in stem cell markers, and Lis1 deletion increased the percentage of HSCs with lineage-specific markers in the absence of cell cycle changes or apoptosis, suggesting a shift toward differentiation. Indeed, in vitro or in vivo deletion of Lis1 stimulated asymmetric daughter cell inheritance of the fate determinant NUMB, a marker of differentiated cells, without affecting NUMB distribution, suggesting an altered plane of cell cleavage. Consistent with these findings, real-time imaging of Lis1-deficient HSCs revealed spindle pole position defects during telophase and uneven inheritance of NUMB, thereby forcing asymmetric division and subsequent differentiation of cells. To determine the role of LIS1-mediated symmetric cell division in tumorigenesis, the authors deleted Lis1 in models of blast crisis CML and de novo AML and found that LIS1 is required for the establishment and maintenance of disease. Moreover, silencing of LIS1 inhibited colony formation and increased differentiation of patient-derived drug-resistant primary CML and AML cells. Together, these results highlight a role for LIS1-mediated regulation of fate determinant inheritance and asymmetric cell division in stem cell maintenance during normal hematopoiesis and in cancer.
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