Adult blood cancers originate decades before diagnosis

23 February, Cambridge – Researchers at Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and EMBL’s European Bioinformatics Institute (EMBL-EBI) have reconstructed the lineage history of individual hematopoietic stem cells (HSCs) obtained from patients suffering from blood cancers known as myeloproliferative neoplasms (MPN). The research, published in the journal Cell Stem Cell, focuses on one specific mutation occurring within HSCs decades before cancer diagnosis.

MPN is thought to originate from a mutation within HSCs, the stem cell which gives rise to all blood cells. This mutation is a single nucleotide change in the JAK2 gene. The mutation, called JAK2-V617F, activates JAK2 signalling, which leads to an increased number of mature blood cells, including red blood cells and platelets.

Here the scientists trace back the disease progression of MPN in individual patients to the initial mutation within a HSC. Strikingly, they find that the mutation occurs decades before diagnosis, at approximately age 9 in a 34 year-old patient, and approximately age 19 in a 63 year-old patient. These findings have implications for both improved MPN diagnosis and potential new treatments using specific inhibitors for the mutation.

A new experimental design

“We developed a method to simultaneously measure both the full transcriptome and somatic mutations of single hematopoietic stem and progenitor cells (HSPCs),” says Sahand Hormoz, Assistant Professor of Systems Biology at Harvard Medical School and Data Science at Dana-Farber Cancer Institute. “We obtained these cells from the bone marrow aspirates of MPN patients allowing us to investigate how the JAK2-V617F mutation impacts HSC differentiation and proliferation in vivo in individual patients.”

The scientists used this method to reconstruct the lineage history of individual HSCs obtained from MPN patients to show the disease expanded in each patient over time. Strikingly, they found that the JAK2-V617F mutation occurred in a single HSC several decades before MPN diagnosis. Subsequently, the population of JAK2 mutant stem cells were shown to grow exponentially every year following this initial mutation.

Clinical implications and future directions

“Our work indicates that JAK2-V617F alone is sufficient to cause MPN,” says Ann Mullally, physician-scientist at Dana-FarberCancer Institute and Brigham and Women’s Hospital. “This provides a compelling motivation for the development of JAK2-V617F mutant-specific inhibitors for more effective and less toxic treatment of MPN in the clinic.”

This new understanding of JAK2 mutations at the onset of MPN progression provides future implications for the prevention and treatment of the disease. These data can also be used in the clinic to aid diagnosis and assess the extent of cancer progression in MPN patients.

“We performed whole-genome sequencing and single-cell profiling on HSPCs from MPN patients,” says Isidro Cortes-Ciriano, Group Leader at EMBL-EBI. “The technology platforms and computational frameworks we developed to reconstruct the lineage tree of these cancer cells are also broadly applicable for use in future studies looking at other types of cancer.”