• CD271-selected mesenchymal stem cells from adipose tissue enhance cartilage repair and are less angiogenic than plastic adherent mesenchymal stem cells

      Kohli, Nupur; Johnson, William Eustace Basil; Uchida, Kenzo; Aston University, University of Chester, University of Fukui (Nature, 2019-02-28)
      CD271 is a marker of bone marrow MSCs with enhanced differentiation capacity for bone or cartilage repair. However, the nature of CD271+ MSCs from adipose tissue (AT) is less well understood. Here, we investigated the differentiation, wound healing and angiogenic capacity of plastic adherent MSCs (PA MSCs) versus CD271+ MSCs from AT. There was no difference in the extent to which PA MSCs and CD271+ MSCs formed osteoblasts, adipocytes or chondrocytes in vitro. In contrast, CD271+ MSCs transplanted into athymic rats significantly enhanced osteochondral wound healing with reduced vascularisation in the repair tissue compared to PA MSCs and control animals; there was little histological evidence of mature articular cartilage formation in all animals. Conditioned medium from CD271+ MSC cultures was less angiogenic than PA MSC conditioned medium, and had little effect on endothelial cell migration or endothelial tubule formation in vitro. The low angiogenic activity of CD271+ MSCs and improved early stage tissue repair of osteochondral lesions when transplanted, along with a comparable differentiation capacity along mesenchymal lineages when induced, suggests that these selected cells are a better candidate than PA MSCs for the repair of cartilaginous tissue.
    • High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia. Leukemia

      Lucas, Claire; Milani, Mateus; Butterworth, Michael; Carmell, Natasha; Scott, Laura; Clark, Richard; Cohen, Gerald; Varadarajan, Shankar; University of Liverpool (Nature, 2016-02-29)
      Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a predictive biomarker of disease progression in many malignancies, including imatinib-treated chronic myeloid leukemia (CML). Although high CIP2A levels correlate with disease progression in CML, the underlying molecular mechanisms remain elusive. In a screen of diagnostic chronic phase samples from patients with high and low CIP2A protein levels, high CIP2A levels correlate with an antiapoptotic phenotype, characterized by downregulation of proapoptotic BCL-2 family members, including BIM, PUMA and HRK, and upregulation of the antiapoptotic protein BCL-XL. These results suggest that the poor prognosis of patients with high CIP2A levels is due to an antiapoptotic phenotype. Disrupting this antiapoptotic phenotype by inhibition of BCL-XL via RNA interference or A-1331852, a novel, potent and BCL-XL-selective inhibitor, resulted in extensive apoptosis either alone or in combination with imatinib, dasatinib or nilotinib, both in cell lines and in primary CD34(+) cells from patients with high levels of CIP2A. These results demonstrate that BCL-XL is the major antiapoptotic survival protein and may be a novel therapeutic target in CML.
    • Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients.

      Lucas, Claire; Harris, Robert; Holcroft, Alison; Scott, Laura; Carmell, Natasha; McDonald, Elizabeth; Polydoros, Fotis; Clark, Richard (Nature, 2015-03-13)
      High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome.