Therapeutic opportunities from dissecting the pre-B leukaemia bone marrow microenvironment

Investigators: Laurence Cheung, Rishi Kotecha, Sebastien Malinge

Collaborators: Jiake Xu (University of Western Australia), Charles Mullighan (St Jude Children's Research Hospital), Bo He (University of Western Australia)

Partners: Children's Leukemia & Cancer Research Foundation (Inc.)

Summary: The advent of precision medicine has revolutionised the treatment of patients with cancer, whereby therapy is tailored to target the abnormal features of a patient’s cancer cells. This has been a successful approach, yet the cure rate is still disappointing in some cancers, which may come back or spread. The immediate environment surrounding cancer cells is well known to influence many stages of cancer progression. It plays an important role in how well treatments work and how cancers spread around the body. Therefore, combinatorial approaches targeting both cancer cells and surrounding cells promises to be an effective strategy to treat patients.

Acute lymphoblastic leukaemia is the most common form of cancer in children, yet the microenvironment of this disease has not been studied in detail. We have established a unique preclinical model for a form of the disease where the survival rates of patients are inferior to most other forms of childhood leukaemia. Using this model, our research focuses on investigating the environment around leukaemia cells, leading to the development of treatments to disrupt the interactions between leukaemia cells and other cells in the surrounding environment.

Project description: 

Acute lymphoblastic leukaemia (ALL) is the most common form of cancer in children. ALL begins in the bone marrow and spreads to the blood and other lymphoid organs. Skeletal abnormalities are commonly seen in children with leukaemia, and more than 35% of patients suffer from musculoskeletal pain at diagnosis. Serum markers of bone formation are low at diagnosis, and bone histomorphometric assessment shows a reduction in trabecular bone volume as well as trabecular thickness prior to initiating chemotherapy, which in turn has further toxic effects to bones. The leukaemogenic process results in bone fragility at the time of leukaemia diagnosis, indicating that the malignant cells have the capacity to alter the microenvironment.

Over the past 20 years clinical studies in children diagnosed with ALL have clearly demonstrated defects in bone marrow microenvironment, yet little is known about the contribution of the normal bone marrow cells during development of the disease, progression and relapse. It remains unclear whether the clinical symptoms of increased bone fragility and reduced bone mineral density should be treated at diagnosis, and whether such treatments would have any impact on leukaemia progression. Studies in acute myeloid leukaemia and myelodysplastic syndromes demonstrate that normalisation of the bone marrow microenvironment reduces disease progression, validating the microenvironment as a potential novel therapeutic target in patients with leukaemia.

We have successfully developed a model that enables the comprehensive investigation of the architecture of bone marrow microenvironment during leukaemogenesis, without incurring damage by irradiation. Importantly, this model recapitulates the clinical symptoms of skeletal abnormalities in children diagnosed with ALL. Using our in vitro and in vivo experimental methods, as well as pharmacologic approaches, this project aims to define in detail the changes of the osteoblastic cells, adipocytes and mesenchymal stem cells during leukaemogenesis. It will focus on the impact of leukaemia cells on the bone marrow microenvironment, and identify novel therapeutic approaches for patients with leukaemia.