A human iPSC derived bone marrow milieu identifies a novel target against niche-conferred leukaemia proliferation and treatment resistance

Pal, D.; Blair, H.; Boyd, S.; Angel, S.; Nizami, S.; Isa, A.; Beckett, M.; Nelson, R.; Wilson, A.; Singh, M.; Sankar, S.; Tirtakusuma, R.; Nakjang, S.; Knill, C.; Fuller, A.; McNeill, H.; Russell, L.; Schwab, C.; Zhou, P.; Sinclair, P.; Coxhead, J.; Filby, A.; Allan, J.; Halsey, C.; Harrison, C.; Moorman, A.; Heidenreich, O.; Vormoor, J.

doi:10.1101/2021.06.18.448490

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bioRxiv · 10.1101/2021.06.18.448490

A human iPSC derived bone marrow milieu identifies a novel target against niche-conferred leukaemia proliferation and treatment resistance

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Abstract

Leukaemia cells re-program their microenvironment to provide proliferation support and protection from standard chemotherapy, molecularly targeted therapies, and immunotherapy. Although much is becoming known about molecules that drive niche-dependent treatment resistance; means of targeting these in the clinics has remained a key obstacle. To address this challenge, we have developed human induced pluripotent stem cell engineered niches ex vivo to reveal insights into druggable cancer-niche dependencies. We show that mesenchymal (iMSC) and vascular niche-like (iANG) cells support ex vivo proliferation of patient-derived leukaemia cells, impact dormancy and mediate therapy resistance. iMSC protected both non-cycling and cycling blasts against dexamethasone treatment while iANG protected only dormant blasts. Leukaemia proliferation and protection from dexamethasone induced-apoptosis was dependent on direct cell-cell contact and mediated by CDH2. To explore the therapeutic potential of disrupting this cell-cell interaction, we tested the CDH2 antagonist ADH-1 (previously in phase I / II for solid tumours) in a very aggressive patient-derived xenograft leukaemia mouse model. ADH-1 showed high in vivo efficacy. ADH-1/ dexamethasone combination therapy was superior to dexamethasone alone with no ADH1 conferred additional toxicity. These findings provide a proof-of-concept starting point to develop novel, potentially safer therapeutics that target niche-mediated cancer cell dependencies in haematological malignancies. SummaryCDH2 mediated niche-dependent cancer proliferation and treatment resistance is clinically targetable via ADH-1, a low toxic agent that could be potentially repurposed for future clinical trials in acute leukaemia.

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Pal, D., Blair, H., Boyd, S., Angel, S., Nizami, S., Isa, A., Beckett, M., Nelson, R., Wilson, A., Singh, M., Sankar, S., Tirtakusuma, R., Nakjang, S., Knill, C., Fuller, A., McNeill, H., Russell, L., Schwab, C., Zhou, P., Sinclair, P., Coxhead, J., Filby, A., Allan, J., Halsey, C., Harrison, C., Moorman, A., Heidenreich, O., Vormoor, J.. 2021-06-18. A human iPSC derived bone marrow milieu identifies a novel target against niche-conferred leukaemia proliferation and treatment resistance. https://doi.org/10.1101/2021.06.18.448490

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