Hematopoietic phenotypes and clonal hematopoiesis in the elderly population (MDS-RIGHT - Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time).

In the previous connected projects OV15-0306, we have sequenced longitudinal samples of 1352 individuals with and without anemia. We were the first to apply sensitive error-corrected targeted sequencing (including 27 genes) at large scale. We developed bioinformatic tools to reliably identify mutations that are present in a small proportion (2%) of blood cells. The data revealed that small somatic clones are surprisingly common in the elderly, with almost 50% of individuals above 60 years of age carrying clonal hematopoiesis. Since most of the analyses are finished, we would now like to extend the project.

Clonal hematopoiesis is used to describe the existence of a genetically distinct subpopulation of blood cells. Sensitive genomic approaches have facilitated extensive mapping of clonal genetic aberrations in a wide range of hematological disorders. We previously reported on mutations in TET2 in MDS (1). Recently, chromosomal copy number alterations (2,3) and somatic mutations (4-6) were discovered to emerge with ageing in healthy individuals. The most commonly mutated genes include DNMT3A, ASXL1 and TET2 (4-6), which are also major molecular aberrations in myeloid hematopoietic malignancies (MDS and AML). CH has now been linked to multiple age-related conditions, including myeloid neoplasms (7,8).

Upon ageing, the hematopoietic system undergoes multiple changes. Ageing individuals show decreased bone marrow cellularity. Another well-known phenomenon is the relative decline in output towards the lymphoid hematopoietic lineage, with a concomitant shift towards myeloid-biased differentiation. Other age-related phenomena include the emergence of anemia and an

increased incidence of myeloid diseases, including leukemia and myelodysplastic syndromes (9). In ageing women, a clonal shift in the output of the hematopoietic system was first demonstrated by skewed X-chromosome inactivation (10,11).

Next-generation sequencing (NGS) is now progressively employed in clinical practice. The technique is included in the diagnostic work-up of several (malignant) hematopoietic conditions, but is also increasingly used for analysis of peripheral blood count abnormalities. However, as the sensitivity of the technique increases, smaller clones may be almost ubiquitous in elderly individuals (12, data from our previous project OV15-0306). Therefore, it is of utmost importance to distinguish “benign” clones from clonal hematopoiesis with diagnostic utility. Moreover, there is need for a better understanding how the emergence of clonal hematopoiesis relates to physiological ageing processes of the hematopoietic system.

The aim of this project is to study the relation between clonal hematopoiesis and hematopoietic (ageing) phenotypes in more detail.