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Both HOXA9 and MEIS1 are required for MLL\u2010fusion gene\u2010induced leukemogenesis. Co\u2010expression of HOXA9 and MEIS1 induces acute myeloid leukemia (AML) similar to that seen in mice in which MLL\u2010fusion genes are over\u2010expressed. p27kip1 (p27 hereafter), a negative regulator of the cell cycle, has also been defined as an MLL target, the expression of which is up\u2010regulated in MLL leukemic cells (LCs). To investigate whether p27 plays a role in the pathogenesis of MLL\u2010leukemia, we examined the effects of p27 deletion (p27\u2212\/\u2212) on MLL\u2010AF9 (MA9)\u2010induced murine AML development. HOXA9\/MEIS1 (H\/M)\u2010induced, p27 wild\u2010type (p27+\/+) and p27\u2212\/\u2212 AML were studied in parallel as controls. We found that LCs from both MA9\u2010AML and H\/M\u2010AML can be separated into three fractions, a CD117\u2010CD11bhi differentiated fraction as well as CD117+CD11bhi and CD117+CD11blo, two less differentiated fractions. The CD117+CD11blo fraction, comprising only 1\u20133% of total LCs, expresses higher levels of early hematopoietic progenitor markers but lower levels of mature myeloid cell markers compared to other populations of LCs. p27 is expressed and is required for maintaining the quiescent and drug\u2010resistant states of the CD117+CD11blo fraction of MA9\u2010LCs but not of H\/M\u2010LCs. p27 deletion significantly compromises the leukemogenic capacity of CD117+CD11blo MA9\u2010LCs by reducing the frequency of leukemic stem cells (LSCs) but does not do so in H\/M\u2010LCs. In addition, we found that p27 is highly expressed and required for cell cycle arrest in the CD117\u2010CD11bhi fraction in both types of LCs. Furthermore, we found that c\u2010Myc expression is required for maintaining LCs in an undifferentiated state independently of proliferation. We concluded that p27 represses the proliferation of LCs, which is specifically required for maintaining the quiescent and drug\u2010resistant states of a small subset of MA9\u2010LSCs in collaboration with the differentiation blockage function of c\u2010Myc.<\/jats:p>","DOI":"10.1016\/j.molonc.2013.07.011","type":"journal-article","created":{"date-parts":[[2013,8,20]],"date-time":"2013-08-20T04:26:01Z","timestamp":1376972761000},"page":"1069-1082","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["p27kip1 maintains a subset of leukemia stem cells in the quiescent state in murine MLL\u2010leukemia"],"prefix":"10.1002","volume":"7","author":[{"given":"Jun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher 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