Title: Unravelling clinical heterogeneity in Philadelphia positive ALL
Funder: Children's Cancer and Leukaemia Group

Abstract: The Philadelphia chromosome results in the BCR-ABL fusion oncoprotein with enhanced tyrosine kinase activity. It is a high-risk cytogenetic abnormality found in approximately 5% of childhood and 25% of adult acute lymphoblastic leukaemias (ALL) and all patients with chronic myeloid leukaemia (CML). Recent reports indicate that Philadelphia chromosome positive ALL (Ph+ALL) can be further sub-divided into a true lymphoid leukaemia with acquisition of the BCR-ABL oncogene in a committed B-cell progenitor (standard Ph+ALL) and a CML-like Ph+ALL with BCR-ABL present in earlier multipotent progenitors. We hypothesise that CML-like and standard Ph+ALL differ transcriptionally and by cell of origin resulting in different responses to therapy, particularly with respect to presence of drug-resistant stem or progenitor cells. This project brings together researchers with strong clinical and preclinical expertise in paediatric and adult ALL and CML. We aim to identify cellular and molecular markers of CML-like Ph+ALL in order to develop clinically useful tools for identifying Ph+ALL subtypes at diagnosis. In addition, we will investigate whether CML-like Ph+ALL requires stem cell directed therapy for cure. In this way we hope to translate our findings rapidly to improve outcomes for patients with CML-like Ph+ALL.

Lay abstract: Defects in genes that control blood cell development are common causes of blood cancers, such as acute lymphoblastic leukaemia. One well-recognised example involves a switch of genes between two chromosomes to produce an abnormal chromosome called the Philadelphia chromosome. This single genetic change can produce at least two types of leukaemia - chronic myeloid leukaemia (CML) and Philadelphia positive acute lymphoblastic leukaemia (Ph+ALL). These two leukaemias are usually thought of as very distinct diseases and have different treatments. However, new scientific research indicates that some (but not all) cases of Ph+ALL share a lot in common with CML. Ph+ALL cases with CML-like features (called CML-like Ph+ALL) appear to be a new sub-type of leukaemia and may need different treatment approaches to enable long-term cure. In this project, we will investigate this newly discovered leukaemia sub-type– CML-like Ph+ALL. We have three experimental aims: 1. To discover whether CML and CML-like Ph+ALL originate in the same types of primitive blood cells located in the bone marrow. This will help us understand how CML-like Ph+ALL develops. 2. To measure the levels of gene expression in the different leukaemia subtypes to see if we can identify a genetic “signature” that allows us to distinguish between Ph+ALL, CML and CML-like Ph+ALL. This will help devise new tests to use in the clinic to identify patients with CML-like Ph+ALL at the time of diagnosis. 3. To test CML-like Ph+ALL cells in the laboratory to see if they will respond to new less toxic therapies that our research team have recently developed to increase long-term cure for patients with CML. In this way, we aim to improve the outlook for patients diagnosed with Ph+ALL, by making sure they get the right diagnosis and treatment.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS