hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia

Pal, Deepali; Blair, Helen J.; Parker, Jessica; Hockney, Sean; Beckett, M; Singh, Mankaran; Tirtakusuma, Ricky; Nelson, Ryan; McNeill, Hesta; Angel, Sharon Hanmy; Wilson, Aaron; Nizami, Salem; Nakjang, Sirintra; Zhou, Peixun; Schwab, Claire; Sinclair, Paul; Russell, Lisa J.; Coxhead, Jonathan; Halsey, Christina; Allan, James M.; Harrison, Christine J.; Moorman, Anthony V.; Heidenreich, Olaf; Vormoor, Josef

doi:10.1016/j.xcrm.2022.100717

Cited by 13 publications

(46 citation statements)

References 96 publications

(133 reference statements)

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“…Explore the impact of human BM cells in driving key elements of cancer biology such as leukaemia proliferation, dormancy and treatment resistance. 14 Importantly, to build proof of confidence in application we show that such human relevant ex vivo platforms have 1. the potential to detect therapeutically exploitable targets that disrupt leukaemia-BM cell interactions conferring treatment resistance to the cancer cells. For example, using our ex vivo approach we reveal that CDH2 drives niche-mediated treatment resistance in leukaemia and that this interaction can be targeted via a drug ADH-1.…”

Section: Introductionmentioning

confidence: 89%

“…Cell lines retain cytogenic characteristics of acute lymphoblastic leukaemia (ALL), but being derived from patients with relapsed disease these samples do not represent the molecular complexity of disease at presentation. 14,15 Cell lines have also artificially adapted to grow in suspension culture which eliminates a key feature of leukaemia biology: microenvironment and its role in treatment resistance. Furthermore, these models are restricted by limited in vivo predictability and often lead to in vitro to in vivo drug attrition rates.…”

Section: Introductionmentioning

confidence: 99%

“…16,17 The niche particularly mesenchyme-blast interaction gives rise to two lymphoblast subpopulations, the first being a slow cycling, dormant population and the second being actively cycling disease propagating blasts. 14,18 Many treatments are effective in reducing the populations of active cycling blasts; however, it is reported that the dormant populations can survive treatment, seeking refuge within the niche. These dormant cells can later shift into the cycling state post treatment, leading to relapse disease.…”

Section: Introductionmentioning

confidence: 99%

“…Mesenchymal cell CXCL12 knockout reversed this change and caused a phenotypic switch into disease propagating cycling blasts, temporarily increasing disease load but allowing once chemo resistant blasts to be treated. 19 In preceding studies, we have developed ex vivo 2D co-culture platforms, 14,15 the purpose of which has been to 1. conduct preclinical drug screening using patientderived leukaemia cells thereby reducing dependence on cell lines and consequently minimising in vitro to in vivo drug attrition rates and 2. Explore the impact of human BM cells in driving key elements of cancer biology such as leukaemia proliferation, dormancy and treatment resistance.…”

Section: Introductionmentioning

confidence: 99%

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A human mesenchymal spheroid prototype to replace moderate severity animal procedures in leukaemia drug testing

Wilson

Hockney²,

Parker³

et al. 2022

F1000Res

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Patient derived xenograft (PDX) models are regarded as gold standard preclinical models in leukaemia research, especially in testing new drug combinations where typically 45-50 mice are used per assay. 9000 animal experiments are performed annually in the UK in leukaemia research with these expensive procedures being classed as moderate severity, meaning they cause significant pain, suffering and visible distress to animal’s state. Furthermore, not all clinical leukaemia samples engraft and when they do data turnaround time can be between 6-12 months. Heavy dependence on animal models is because clinical leukaemia samples do not proliferate in vitro. Alternative cell line models though popular for drug testing are not biomimetic – they are not dependent on the microenvironment for survival, growth and treatment response and being derived from relapse samples they do not capture the molecular complexity observed at disease presentation. Here we have developed an in vitro platform to rapidly establish co-cultures of patient-derived leukaemia cells with 3D bone marrow mesenchyme spheroids, BM-MSC-spheroids. We optimise protocols for developing MSC-spheroid leukaemia co-culture using clinical samples and deliver drug response data within a week. Using three patient samples representing distinct cytogenetics we show that patient-derived-leukaemia cells show enhanced proliferation when co-cultured with MSC-spheroids. In addition, MSC-spheroids provided improved protection against treatment. This makes our spheroids suitable to model treatment resistance – a major hurdle in current day cancer management Given this 3Rs approach is 12 months faster (in delivering clinical data), is a human cell-based biomimetic model and uses 45-50 fewer animals/drug-response assay the anticipated target end-users would include academia and pharmaceutical industry. This animal replacement prototype would facilitate clinically translatable research to be performed with greater ethical, social and financial sustainability.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A human mesenchymal spheroid prototype to replace moderate severity animal procedures in leukaemia drug testing

Wilson

Hockney²,

Parker³

et al. 2022

F1000Res

Self Cite

View full text Add to dashboard Cite

show abstract

“…have recreated the bone marrow niche using induced pluripotent stem cells (iPSCs), identifying CDH2 as a therapeutically druggable leukemia-promoting factor. 1 …”

mentioning

confidence: 99%