The role of the bone marrow niche in the maintenance of cancer stem cells in chronic myeloid leukaemia (CML)

Developing cancer therapies that eradicate cancer stem cells (CSC) and cure the disease is hugely challenging. This is exemplified in chronic myeloid leukaemia (CML), an advanced paradigm of CSC research, where BCR-ABL1 transforms a normal haemopoietic stem cell (HSC) into a leukaemic stem cell (LSC). Most CML patients present in chronic phase (CP), during which BCR-ABL1 drives molecular changes in the LSC that may increase their "fitness" and drive their clonal expansion according to Darwinian principles. In worse case scenarios, these changes result in total resistance to standard-of-care tyrosine kinase inhibitors (TKI) and promotes disease progression to accelerated phase and then to terminal blast phase. The key bottleneck to curing CML is the sub-population(s) of LSC in the bone marrow (BM) that persists throughout TKI treatment, it is these populations in which drug resistance and disease progression occur. TKI-resistant LSCs sustain residual CML in patients, drive TKI-resistance and disease progression through clonal evolution and allows for relapse upon TKI discontinuation.
To date, our knowledge of LSC biology has been based on analysis of bulk cell populations taken from patient samples at diagnosis or relapse. However, for TKI-resistant LSC in patients on TKI, we know very little about the molecular mechanisms of how they evolve, what pathways they require, and how they vary among patients. This is because (1) the TKI-resistant LSC are extremely rare in the BM (particularly in MMR), and (2) to date, LSC cannot be selectively isolated from normal HSC that reconstitute normal haemopoiesis in the BM during TKI therapy. For these reasons, it is not surprising that, despite the identification of more than 40 drug targets in LSC over the last 15 years, relatively few drugs reach clinical trials, and none have replaced, or even supplemented TKI as the standard-of-care.
Holyoake was the first to demonstrate that CML-CSCs are not oncogene-addicted. Since 2007, Holyoake, et al have compiled (LEUKomics, CML-specific domain within STEMFORMATICS, >30 in-house/public multi-omics datasets describing CML-CSCs. LSCs do not require BCR-ABL-kinase activity for survival, nor do they have BCR-ABL kinase domain mutations in patients during CP, inferring that they survive through BCR-ABL-kinase-independent pathways. Data-mining has revealed three key hubs (p53, c-Myc, PRC2) controlling a targetable CML-CSC intrinsic network. Demonstrating interactions between CML-CSC and their BM microenvironment, revealing cytokines/chemokines, JAK/STAT, N-cadherin/WNT/b-catenin and hedgehog signalling as potential key players.
Using the murine stem cell leukaemia (SCL) gene 3' enhancer, transactivator protein (Tta), BCR-ABL (SCL-tTA-BCR-ABL) model we will be able to induce BCR-ABL expression via tetracycline withdrawal (driven off SCL promotion), which resembles chronic phase CML. Extending current collaborations to provide a comprehensive transcriptomic landscape of CML-CSC and key BM niche components that support CSC. My research will:
1. Determine which niche cell subsets (mesenchymal stem cells (MSC) and macrophages) support CML-CSCs altering the disease kinetics of CML and TKI-response in a well-described CML transgenic (SCL-tTA-BCR-ABL) mouse model
2. Determine whether CML-CSC are dependent (in terms of disease initiation, maintenance, response to therapy and relapse) on either MSC or macrophages within the BM/spleen niche. Positive findings would then be investigated in human CML samples and in the xenograft NSG model, using the CML biobank, the largest of its kind worldwide.