Despite substantial improvements in treatment of older children, new research has begun to unravel the mystery of why a particular type of leukaemia in infants has defied efforts to improve outcomes. Despite the wellcome Sanger Institute, Great Ormond Street Hospital, Newcastle University, and their collaborators discovered subtle differences in the cell type that causes B acute lymphoblastic leukaemia (B-ALL), which may help explain why some instances are more severe.
Then, the research was published today (14 March 2022) in Nature Medicine, focused on the majority of infant B-ALL cases caused by modifications to theKMT2Agene. These findings provide a number of promising drug targets, indicating that effective therapies for infant B-ALL might be developed in the future.
Acute lymphoblastic leukaemia (ALL) can vary in length depending on the cell type involved. These cancers arise when cells break up from haematopoietic stem cells to mature blood cells. In the case of B-ALL, disease is caused by a type of immune cell called B lymphocytes, more commonly known as B cells.
B-ALL in children was once a universally fatal illness that is now curable in the majority of cases1. An exception is B-ALL in children under one year of age, where treatment has been successful in less than 50% of cases, with no significant improvement in the last two decades. Treatments that have been proven in tackling other forms of leukaemia, such as bone marrow transplants, have proven ineffective against infant B-ALL. It is currently treated with a powerful therapy, which can be difficult for the patient
Researchers used cancer cells to identify normal human blood cells in 1,665 childhood leukaemia patients. Using single-cell mRNA samples from around 60,000 normal fetal bone marrow cells2, they used the KMT2A-rearranged infant B-ALL technique.
Analyse found that infant B-ALL showed distinct cellular signals, indicating that early lymphocyte precursors (ELPs)3 were important components, which is an immature immune cell type that normally develops into B cells.
Leukaemias are usually classified by the type of cell in which the disease is involved, and in the case of B acute lymphoblastic leukaemia (B-ALL), we discuss B cell progenitors. However, our research into this disease has shown that this is actually a early lymphocyte precursor leukaemia.
Dr Laura Jardine, the first author of the research from Newcastle University, is a student.
The researchers found that as an ELP cell progresses towards becoming a mature B cell, the greater the outcome for the patient.
As part of this research, we have unimagined why B acute lymphoblastic leukaemia (B-ALL) is more responsive to treatment in some children, but why it is not so successful for infants. Cancers with more mature early lymphocyte precursors (ELPs) seem to respond better to treatment. These more mature cells are more common in B-ALL in older adults, but unfortunately not for our younger patients, meaning the treatment is less effective. The challenge is now to develop our understanding and confirm these suspicions
Dr Jack Bartram, a senior author of the study from the Great Ormond Street Hospital, is a professor.
Researchers compared gene expression profiles of the cancer to those of normal ELP cells, suggesting a malfunction in the normal process of differentiation. Multiple biological pathways and markers were identified in thishybrid ELP cells that might lead to promising therapeutic results.
Although it is too early to draw conclusions about why B acute lymphoblastic leukaemia (B-ALL) has significantly poorer outcomes in infants than in older children, this study provides compelling evidence that the maturity of certain cancers is a major factor. These data will help us better understand the severity of illness and determine the best treatment option.
Dr Sam Behjati, a senior author of the Wellcome Sanger Institute research, has been a contributing researcher.
1. Visit the Cancer Research UK website for more information on acute lymphoblastic leukaemia and how the normal development of blood cells might be slowed.
2. A collaboration collaboration with the Human Cell Atlas (HCA) project is constructing comprehensive reference maps of all human cells as a basis for understanding human health and for diagnosing, monitoring, and treating disease. https://www.humancellatlas.org
3. ELPs are a type of lymphoid cell that has the capability to differentiate into other types of lymphocytes. ELPs also have the ability to differentiate into bone marrow cells.