Editors' ChoiceCancer

The Heart of “Stemness”

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Science Translational Medicine  18 Aug 2010:
Vol. 2, Issue 45, pp. 45ec130
DOI: 10.1126/scitranslmed.3001569

Asymmetry is at the heart of “stemness.” In order to be a stem cell, a cell must be able to give rise to two different daughters: one that will go on to become a progenitor cell and subsequently differentiate, whereas the other must remain a stem cell. These two paths must be in perfect balance in order to keep the number of stem cells constant. It has long been suspected that in leukemia, this balance is perturbed. Chronic myelogenous leukemia (CML) is characterized by increased numbers of myeloid cells in circulation. These cells universally carry the BCR-ABL translocation, which has been shown to promote differentiation along the myeloid lineage. However, eventually this chronic phase leads to a “blast crisis” akin to acute leukemia, with undifferentiated cells beginning to predominate. Now, a “second hit” can be detected in these cells—commonly another translocation such as Nup98-HoxA9—but how this mutation causes blast crisis has remained a mystery.

The groups led by Daley and Reya now shed light on this transition. Through independent approaches, both groups converge on a gene called Musashi-2, named after a Japanese two-sworded warrior because the original Drosophila mutation in the Musashi homolog had two bristles instead of one. Musashi was already known to be the “pro-symmetry” factor regulating the asymmetric cell division in nonhematopoietic tissues. Daley’s group now shows that Musashi-2 overexpression in mouse bone marrow leads to an expansion of the stem cell pool at the expense of the myeloid lineage, which is reminiscent of the blast crisis stage of CML. Both groups demonstrate that high levels of Mushashi-2 in human acute leukemia cells portend a poor prognosis, whereas disrupting Musashi-2 prevents aggressive leukemia. What turns on Musashi-2 in leukemic cells? Reya’s group demonstrates that Nup98-HoxA9 directly turns on Musashi-2 expression, which in turn skews the stem cell division towards self-renewal, leading to an expansion of stem cells that manifests as blast crisis. The authors propose that targeting Musashi-2 in aggressive leukemia may help restore the balance of stem cell division that appears to be at the heart of this challenging illness.

M. G. Kharas et al., Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat. Med. 16, 903–908 (2010). [Full Text]

T. Ito et al., Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 466, 765–768 (2010). [Abstract]

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