Clonal hematopoiesis (CH) refers to competitive growth advantage and expansion of a bone marrow hematopoietic stem cell clone. Outside the context of an overt hematological malignancy, CH is characterised by the presence of mutations in genes such as DNMT3A and TET2 (CH of indeterminate potential, CHIP), or as mosaic chromosomal alterations (acquired chromosomal deletions, duplications, or copy number neutral loss of heterozygosity, collectively referred to as mosaic chromosomal alterations (mCAs)). The prevalence of CH increases with age, and 10-20% of individuals harbor a CHIP clone by age 70 years. CH portends increased all-cause mortality and increased risk of hematological malignancies. CH may also promote inflammation in cardiovascular diseases; however, the role of CH in other disease conditions remains to be fully elucidated.
Systemic inflammation involving abnormal activation of the innate and adaptive immune compartments is a hallmark of various disease entities with significant health burden globally. The mechanisms regulating inflammatory processes in both autoimmune and non-autoimmune diseases are not fully understood. In this context, clonal hematopoiesis (CH) has been described to affect age-related diseases and may represent a key factor influencing the development and severity of inflammatory conditions.
To understand the association between CH and inflammation, our research group leverages genetic information from whole exome sequencing, DNA microarrays, and targeted next-generation sequencing panels in population-level biobank projects as well as in disease-specific patient cohorts to identify specific CH subtypes linked with disease phenotypes and outcomes.
We also aim to elucidate the functional basis of these associations using 1) CRISPR/Cas9 gene editing in cell lines, 2) functional studies in induced pluripotent stem cell (iPSC) -derived immune cell cultures, and 3) single cell multiomics approaches in patient samples.
Understanding the interplay between CH and inflammatory diseases can lead to new insights into disease pathophysiology, new therapeutic approaches, and improved prediction of patient outcomes.
In addition to environmental exposures, inherited genetic factors may also shape the expansion of mutated stem cell clones in the bone marrow. This phenomenon is particularly evident in patients with inherited bone marrow failure syndromes (IBMFS) that are characterised by low peripheral blood cell counts due to decreased blood cell production. While genetically diverse, bone marrow stem cells frequently acquire mutations that improve cell fitness in IBMFS, a phenomenon known as somatic compensation. Somatic compensation can occur via distinct genetic processes such as loss of the germline mutation or somatic alterations in pathways affected by the disease-causing gene.
One of our projects focuses on somatic compensation in cartilage-hair hypoplasia (CHH), an inherited disorder highly enriched in the Finnish population that commonly represents with short stature, skeletal abnormalities, immunodeficiency, and hypoplastic anemia in newborns.
While the clinical implications of somatic compensation in IBMFS remain to be fully discovered, understanding these mutational processes can help understand disease pathophysiology and may inform future diagnostic and therapeutic approaches.
Circulating tumor DNA (ctDNA) detected in peripheral blood is a promising novel marker for response prediction in solid cancer patients. Measurement of ctDNA relies on the detection of somatic cancer mutations which is potentially compromised by a biological background arising from clonal hematopoiesis. Indeed, the majority of cell-free DNA (cfDNA) is derived from hematopoietic cells in healthy individuals and many mutations in the cfDNA represent clonal hematopoiesis in solid tumor patients. However, the confounding role of CH has not been comprehensively characterised and other associations between ctDNA features and CH remain to be elucidated.
In our project, we aim to comprehensively evaluate the association between clonal hematopoiesis mutations in peripheral blood and ctDNA content and their impact on treatment outcomes in patients with high-risk lymphoma.
Complete understanding of cfDNA composition is seminal to make longitudinal tracking of ctDNA content clinically actionable in cancer patients.