p27kip1 maintains a subset of leukemia stem cells in the quiescent state in murine MLL‐leukemia

Abstract

MLL (mixed-lineage leukemia)-fusion genes induce the development of leukemia through deregulation of normal MLL target genes, such as HOXA9 and MEIS1. Both HOXA9 and MEIS1 are required for MLL-fusion gene-induced leukemogenesis. Co-expression of HOXA9 and MEIS1 induces acute myeloid leukemia (AML) similar to that seen in mice in which MLL-fusion genes are over-expressed. p27kip1 (p27 hereafter), a negative regulator of the cell cycle, has also been defined as an MLL target, the expression of which is up-regulated in MLL leukemic cells (LCs). To investigate whether p27 plays a role in the pathogenesis of MLL-leukemia, we examined the effects of p27 deletion (p27-/-) on MLL-AF9 (MA9)-induced murine AML development. HOXA9/MEIS1 (H/M)-induced, p27 wild-type (p27+/+) and p27-/- AML were studied in parallel as controls. We found that LCs from both MA9-AML and H/M-AML can be separated into three fractions, a CD117-CD11bhi differentiated fraction as well as CD117+CD11bhi and CD117+CD11blo, two less differentiated fractions. The CD117+CD11blo fraction, comprising only 1-3% 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-resistant states of the CD117+CD11blo fraction of MA9-LCs but not of H/M-LCs. p27 deletion significantly compromises the leukemogenic capacity of CD117+CD11blo MA9-LCs by reducing the frequency of leukemic stem cells (LSCs) but does not do so in H/M-LCs. In addition, we found that p27 is highly expressed and required for cell cycle arrest in the CD117-CD11bhi fraction in both types of LCs. Furthermore, we found that c-Myc 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-resistant states of a small subset of MA9-LSCs in collaboration with the differentiation blockage function of c-Myc.

Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway

“…3b). The undifferentiated CD117 + CD11B low population 35 was significantly reduced in both RIP1 −/− and RIP3 −/− AML cells compared to WT AML cells. Both RIP1 −/− and RIP3 −/− AML cells express increased levels of the differentiation marker CD11b compared to WT AML cells (Fig.…”

Proteasome Inhibitors Evoke Latent Tumor Suppression Programs in Pro-B MLL Leukemias through MLL-AF4

“…Is this a necessity or simply an unwanted byproduct? In favor of the first scenario, it has been suggested that low level of p27 induction by MLL-fusion proteins might prevent leukemia initiating cells from exhaustion (Zhang et al, 2013). In favor of the second scenario, MLL-fusions unavoidably acquire this context-dependent tumor suppressor activity through the common MLL amino-terminus.…”

MLL-TET1 fusion protein promotes immortalization of myeloid progenitor cells and leukemia development

“…This indicate the possibility of a phenotypic inter-convertibility between CD117 + CD11b hi and CD117 + CD11b lo MA9 leukemic cells. 12 The above phenomenon appears to have also occurred in MT1 cells.…”