Molecular and cellular mechanisms of chemoresistance in paediatric pre-B cell acute lymphoblastic leukaemia.

Paediatric patients with relapsed B cell acute lymphoblastic leukaemia (B-ALL) have poor prognosis, as relapse-causing clones are often refractory to common chemotherapeutics. While the molecular mechanisms leading to chemoresistance are varied, significant evidence suggests interactions between B-ALL blasts and cells within the bone marrow microenvironment modulate chemotherapy sensitivity. Importantly, bone marrow mesenchymal stem cells (BM-MSCs) and BM adipocytes are known to support B-ALL cells through multiple distinct molecular mechanisms. This review discusses the contribution of integrin-mediated B-ALL/BM-MSC signalling and asparagine supplementation in B-ALL chemoresistance. In addition, the role of adipocytes in sequestering anthracyclines and generating a BM niche favourable for B-ALL survival is explored. Furthermore, this review discusses the role of BM-MSCs and adipocytes in promoting a quiescent and chemoresistant B-ALL phenotype. Novel treatments which target these mechanisms are discussed herein, and are needed to improve dismal outcomes in patients with relapsed/refractory disease.

Expression of the chemokine receptor CCR1 decreases sensitivity to bortezomib in multiple myeloma cell lines.

BACKGROUND: The proteasome inhibitor bortezomib is one of the primary therapies used for the haematological malignancy multiple myeloma (MM). However, intrinsic or acquired resistance to bortezomib, via mechanisms that are not fully elucidated, is a barrier to successful treatment in many patients. Our previous studies have shown that elevated expression of the chemokine receptor CCR1 in MM plasma cells in newly diagnosed MM patients is associated with poor prognosis. Here, we hypothesised that the poor prognosis conferred by CCR1 expression is, in part, due to a CCR1-mediated decrease in MM plasma cell sensitivity to bortezomib. METHODS: In order to investigate the role of CCR1 in MM cells, CCR1 was knocked out in human myeloma cell lines OPM2 and U266 using CRISPR-Cas9. Additionally, CCR1 was overexpressed in the mouse MM cell line 5TGM1. The effect of bortezomib on CCR1 knockout or CCR1-overexpressing cells was then assessed by WST-1 assay, with or without CCL3 siRNA knockdown or addition of recombinant human CCL3. NSG mice were inoculated intratibially with OPM2-CCR1KO cells and were treated with 0.7 mg/kg bortezomib or vehicle twice per week for 3 weeks and GFP+ tumour cells in the bone marrow were quantitated by flow cytometry. The effect of CCR1 overexpression or knockout on unfolded protein response pathways was assessed using qPCR for ATF4, HSPA5, XBP1, ERN1 and CHOP and Western blot for IRE1α and p-Jnk. RESULTS: Using CCR1 overexpression or CRIPSR-Cas9-mediated CCR1 knockout in MM cell lines, we found that CCR1 expression significantly decreases sensitivity to bortezomib in vitro, independent of the CCR1 ligand CCL3. In addition, CCR1 knockout rendered the human MM cell line OPM2 more sensitive to bortezomib in an intratibial MM model in NSG mice in vivo. Moreover, CCR1 expression negatively regulated the expression of the unfolded protein response receptor IRE1 and downstream target gene XBP1, suggesting this pathway may be responsible for the decreased bortezomib sensitivity of CCR1-expressing cells. CONCLUSIONS: Taken together, these studies suggest that CCR1 expression may be associated with decreased response to bortezomib in MM cell lines.

More than a small adult brain: Lessons from chemotherapy-induced cognitive impairment for modelling paediatric brain disorders.

Childhood is recognised as a period of immense physical and emotional development, and this, in part, is driven by underlying neurophysiological transformations. These neurodevelopmental processes are unique to the paediatric brain and are facilitated by augmented rates of neuroplasticity and expanded neural stem cell populations within neurogenic niches. However, given the immaturity of the developing central nervous system, innate protective mechanisms such as neuroimmune and antioxidant responses are functionally naïve which results in periods of heightened sensitivity to neurotoxic insult. This is highly relevant in the context of paediatric cancer, and in particular, the neurocognitive symptoms associated with treatment, such as surgery, radio- and chemotherapy. The vulnerability of the developing brain may increase susceptibility to damage and persistent symptomology, aligning with reports of more severe neurocognitive dysfunction in children compared to adults. It is therefore surprising, given this intensified neurocognitive burden, that most of the pre-clinical, mechanistic research focuses exclusively on adult populations and extrapolates findings to paediatric cohorts. Given this dearth of age-specific research, throughout this review we will draw comparisons with neurodevelopmental disorders which share comparable pathways to cancer treatment related side-effects. Furthermore, we will examine the unique nuances of the paediatric brain along with the somatic systems which influence neurological function. In doing so, we will highlight the importance of developing in vitro and in vivo paediatric disease models to produce age-specific discovery and clinically translatable research.