Deepali Pal

Newcastle University | NCL · Northern Institute for Cancer Research

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, m...

Improved and low toxicity treatments are urgently required to treat cancers, however cancer drug development is hindered by high drug attrition rates. Lack of tractable, reproducible, and transferrable platforms are key impediments hindering cancer drug development. Here we develop a prototype ECM, Vitronectin Alginate Laminin (VAL), comprised of a...

This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia–niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challen...

Cancer therapies have several clinical challenges associated with them, namely treatment toxicity, treatment resistance and relapse. Due to factors ranging from patient profiles to the tumour microenvironment (TME), there are several hurdles to overcome in developing effective treatments that have low toxicity that can mitigate emergence of resista...

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, m...

Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (i...

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakp...

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 animals are used per assay. 9000 animal experiments are performed annually in leukaemia research with these expensive procedures being described as moderate severity, meanin...

The fusion gene MLL-AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. However, relapse can be associated with a switch from acute lymphoblastic to acute myeloid leukaemia. Here we show that these myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate in either early, mult...

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 addr...

Acute lymphoblastic leukemia (ALL) is the most common type of childhood leukaemia. Recently improved risk stratification resulted in therapy optimization and extended survival for the majority of cases. Unfortunately, there is still a significant number of patients either relapsing or not responding to treatment with response to glucocorticoids bei...

The translocation MLL-AF4 defines a high-risk subtype of acute leukaemia which, uniquely amongst MLL translocations, is almost exclusively associated with a pro-B lymphoid phenotype. However, the ability to switch lineage at relapse allowed interrogation of the cellular origin and lineage determinants of this leukaemia. The origin of MLL-AF4 lympho...

Background Childhood acute lymphoblastic leukaemia (ALL) responds well to conventional treatment, however there is a need to find more targeted therapies without the associated toxicities. There is great inconsistency of drug responses in cell lines, and often these do not represent the outcomes observed in the clinic. Patient‐derived xenografts (P...

Background B‐cell acute lymphoblastic leukemia (B‐ALL) is a heterogeneous hematological disorder characterized by accumulation of B cell precursors. Although undeniable improvement has been made in the therapy of B‐ALL (>90% of pediatric patients experience remission), there are still specific subtypes associated with poor outcome. Among such subty...

Fig. S1. BM‐MSC validation. Fig. S2. The effects of AUR/ADE on normal and malignant cells. Fig. S3. AUR induces ROS levels in SEM cell line. Fig. S4. ADE increases oxidative stress in BCP‐ALL cell lines. Fig. S5. Catalase partially reverses AUR‐induced cell death. Fig. S6. Pyruvate and catalase prevent AUR‐mediated ROS induction. Fig. S7. AUR...

Table S1. EC50 and EC80 of AUR and ADE for BCP‐ALL cell lines representing distinct subtypes of BCP‐ALL. Table S2. EC50 of AUR and ADE for BCP‐ALL primograft cells treated in mono‐ and coculture with primary BM‐MSC. Table S3. Clinical and biological characteristics of pediatric BCP‐ALL patients enrolled into TXN system genes expression analysis....

B cell precursor acute lymphoblastic leukemia (BCP‐ALL) is a genetically heterogeneous blood cancer characterized by abnormal expansion of immature B cells. Although intensive chemotherapy provides high cure rates in a majority of patients, subtypes harboring certain genetic lesions, such as MLL rearrangements or BCR‐ABL1 fusion, remain clinically...

Main Text: (Cancer Cell 34, 626–642.e1–e8; October 8, 2018) During the preparation of the manuscript, we inadvertently left out Dr. Cameron Osborne, who was an important contributor to the chromatin capture experiments described in our article. His contribution is now included in the Author Contributions section, and his name has been added to the...

Advances in three-dimensional (3D) cell cultures offer new opportunities in biomedical research and drug development. However, there are still challenges to overcome, including the lack of reliability, repeatability and complexity of tissues obtained by these techniques. In this study, we describe a new bioprinting system called Reactive Jet Imping...

Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyc...

Key Points Loss of ATR signaling is cytotoxic to AML cells in combination with gemcitabine and hydroxyurea via the induction of replication stress. A small molecule inhibitor of ATR in combination with gemcitabine completely eradicates AML in an orthotopic xenograft mouse model.

High frequencies of blasts in primary acute lymphoblastic leukaemia (ALL) samples have the potential to induce leukaemia and to engraft mice. However it is unclear how individual ALL cells each contribute to drive leukaemic development in a bulk transplant and the extent to which these blasts vary functionally. We used cellular barcoding as a fate...

Temporary single cell coating is a useful tool for cell processing, allowing manipulation of cells to prevent cell attachment and agglomeration, before re-establishing normal cell function. In this paper, a speckled coating method using a known polycation (poly-L-lysine, PLL) is described to induce cell surface electrostatic charges on three differ...

The ataxia telangiectasia and RAD3-related (ATR) protein kinase is a component of the cellular DNA damage response pathway and promotes cell survival by signalling repair of collapsed replication forks generated by replication stress. We hypothesised that inhibition of ATR potentiates the anti-leukaemic activity of chain terminating nucleoside anal...

this issue of Cancer Cell, Ebinger et al. describe rare, non-cycling blasts in acute lymphoblastic leukemia that combine the phenotypes of dormancy, sternness, and chemo-resistance. This novel in vivo model for dormant blasts will facilitate the dissection of the niche and the development of therapies targeting the leukemic microenvironment.

Introduction: Investigating gain of drug resistance in ALL is complicated by questions about a suitable model, cell lines are by and large not drug naive and patient material does not grow well in vitro. To this end we have sought to show that CRISR Cas9 genome editing technology can be used in patient derived ALL material in vivo to study emergenc...

Lack of suitable in vitro culture conditions for primary acute lymphoblastic leukaemia (ALL) cells severely impairs their experimental accessibility and the testing of new drugs on cell material reflecting clonal heterogeneity in patients. We show that Nestin-positive human mesenchymal stem cells (MSC) support expansion of a range of biologically a...

Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.

Although paediatric acute lymphoblastic leukaemia (ALL) has a favourable prognosis, a number of cases will invariably relapse. One of the major problems associated with relapse is drug resistance, in particular to glucocorticoids, the mainstay of ALL treatment. Examining the underlying mechanisms is complicated by clonal heterogeneity within a pati...

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and adolescents where treatment is associated with significant morbidity. Novel therapeutic approaches to improve treatment outcome and minimize side-effects are therefore required. We have previously shown a lack of stem cell hierarchy and a high frequency of leukemic ste...

Background We reviewed the empirical use of antibiotics in patients with secondary haemorrhage following transurethral resection of bladder tumour. Patients and methods A retrospective review of 2830 patients undergoing TURBT between January 2006 and April 2009 was performed from two large independent urology centres in the UK. Patients with secon...