IRB Barcelona researchers discover genetic drivers of clonal hematopoiesis

Clonal hematopoiesis is a biological process in which a blood stem cell (the population that gives rise to different types of blood cells) acquires a beneficial mutation and outgrows neighboring cells. Clonal hematopoiesis is diagnosed when this mutation is present in 2% of all blood cells in a given individual. The beneficial mutations driving clonal hematopoiesis are positively selected, as are mutations in cancer genes responsible for the malignancy of cells.

Led by ICREA research professor Dr. Núria López-Bigas, scientists in IRB Barcelona’s Biomedical Genomics lab have reused computer tools originally designed in the field of cancer genomics to locate the genes that drive clonal hematopoiesis. The rationale behind this strategy is that the development of both cancer and clonal hematopoiesis is subject to positive selection, and therefore, if appropriately adapted, tools and datasets used to identify genes driving cancer, also the research of clonal hematopoiesis. can promote.

First, to identify somatic mutations in blood cells, the researchers reversed the methodology used in cancer, which uses the genome of blood cells from a cancer patient as a reference to identify the somatic mutations in the tumor sample. Instead, they performed a “reverse call,” that is, they used the tumor genomes as references to identify somatic mutations present in blood cell genomes, which had expanded as a result of clonal hematopoiesis. Using the Integrative OncoGenomics (IntOGen) pipeline developed by the group, they used these blood somatic mutations to identify genes under positive selection in clonal hematopoiesis.

Clonal hematopoiesis was first identified more than 60 years ago, but a complete understanding of all the genes that can cause this condition is still lacking.

“In this work, we propose a novel approach that could lead to the identification of the compendium of its driver genes, improving our understanding of the underlying mechanisms and contributing to the early detection of clonal hematopoiesis in the population,” says dr. Abel. González-Pérez, an IRB Barcelona research associate who, along with Dr. López-Bigas led the project.

Clonal hematopoiesis as a global health problem

Clonal hematopoiesis is a process closely related to aging, and cancer patients who have undergone chemotherapy are also more likely to develop this condition.

In previous work, we have studied the evolution of blood cells during cancer treatment and observed how, although the onset of clonal hematopoiesis occurs before exposure to chemotherapy, the treatment favors this process.”

dr. Oriol Pich, lead author of the study and IRB Barcelona Alumni, currently a postdoctoral researcher at the Francis Crick Institute, London

Clonal hematopoiesis, although not a disease, increases the chances of developing blood malignancies and various cardiovascular conditions later in life. Early detection and subsequent monitoring are therefore key to early and proper monitoring and treatment of related complications.

The Biomedical Genomics lab is now participating in two research projects assessing the impact of clonal hematopoiesis on the healthy population, particularly with regard to atherosclerosis and myocardial infarction.

This study was made possible thanks to the patients (and their families) who donated samples for scientific research, and cancer genomics scientists who laboriously analyzed them and made their sequences available in the public domain. This work involved three specific cohorts of donors, contributed by TCGA, the Hartwig Medical Foundation and MSK-IMPACT, respectively.
The study received funding from the European Research Council, the Spanish Ministry of Science and the Spanish Cancer Society (AECC).


Reference magazine:

Pich, O., et al. (2022) Discovering the drivers of clonal hematopoiesis. Nature Communication.

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