Using induced pluripotent stem cells as a replacement for in vivo models to screen novel therapies which target self-renewal pathways in chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) is often described as a paradigm for the cancer stem cell hypothesis. CML develops when a multipotent haemopoietic stem cell (HSC) acquires the Philadelphia chromosome (Ph), a reciprocal translocation between the long arms of chromosomes 9 and 22, designated t(9;22)(q34;q11). The result is the expression of a constitutively active tyrosine kinase called BCR-ABL, the putative cause of CML.

Emerging evidence indicates that CML is sustained by a small pool of highly quiescent cancer stem cells (CSCs), with self-renewing capacity, which reside within the bone marrow niche. These primitive CSCs are insensitive to treatment including specific BCR-ABL tyrosine kinase inhibitor (TKI) therapy (imatinib, dasatinib, nilotinib, bosutinib), making them difficult to eradicate. Recent interest has focused on dual targeting methods inhibiting BCR-ABL tyrosine kinase activity in combination with specific small-molecule inhibitors, which target conserved self-renewal pathways (Wnt, Hedgehog [Hh], bone morphogenic protein [BMP], transforming growth factor-ß [TGFß] and Notch pathways). However obtaining sufficient numbers of these CSCs to perform the detailed biochemistry analysis necessary to determine efficacy of these potential treatments is proving difficult.

Induced pluripotent stem cells (iPSC) have the potential to solve this problem. Generating disease-specific iPSC from patient cells will allow us to produce both primitive CSCs and more differentiated progeny for drug discovery in CML. This ideal model will enable the efficacy of individual drug treatments versus combination treatments to be evaluated at multiple levels and more importantly their ability to eradicate the most primitive CSC populations responsible for minimal residual disease, relapse and disease progression. Studies suggest that identifying agents that specifically target the CSCs is likely to be essential for the elimination (cure) of leukaemia.

Toofan P et al. (2018). Chronic myeloid leukaemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal. Cell Death & Disease 9(9):927. doi: 10.1038/s41419-018-0905-2

Toofan P, Wheadon H (2016). Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis. Biochem Soc Trans 44(5):1455-63. doi: 10.1042/BST20160104

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PhD Studentship

Status

Closed

Principal investigator

Dr Helen Wheadon

Institution

University of Glasgow

Co-Investigator

Dr Mhairi Copland

Grant reference number

NC/K500331/1

Award date

Jul 2012 - Jul 2016

Grant amount

£120,000