Research projects
Dr. Kirschner's Stem Cell Aging and Cancer Lab has several research projects.
Clonal hemopoiesis
Clonal hematopoiesis is a bone marrow disorder characterized by the presence of pathogenic mutations in hematopoietic stem and progenitor cells detectable in the blood. It occurs in about 10% to 20% of people age 60 and older.
The expansion of these mutations is linked to increased risks of hematological cancers, cardiovascular conditions, neurodegenerative disorders and overall mortality, with age being a significant risk factor.
Predictive tools are needed to help assess the risk of clonal hematopoiesis progressing to cancer or other conditions. These tools would help healthcare professionals make informed decisions about disease monitoring, preventive care, early diagnosis and personalized treatment.
In previous research, Dr. Kirschner's lab demonstrated that clonal hematopoiesis mutations contributed to premature aging in the Lothian Birth Cohorts, which are two long-term studies of aging. The team observed an increase in epigenetic age, which is a measure of biological age.
More recently, the lab conducted a study of the Lothian Birth Cohorts using longitudinal data over a 15-year time span. The team developed a new filter to detect clonal hematopoiesis mutations in participants 70 to 90 years old. Through modeling and machine learning, the team estimated the growth rate of clonal hematopoiesis clones, referred to as clonal fitness, and identified gene-specific fitness effects for commonly mutated clonal hematopoiesis genes, helping stratify participant outcomes.
Dr Kirschner found that mutations in epigenetic regulators such as DNMT3A and TET2, though the most common clonal hematopoiesis mutations, confer relatively modest fitness advantages. In contrast, splicing mutations such as SF3B1 and SRSF2, though rarer, provide a significant fitness advantage, leading to rapid clonal expansion.
The temporal dynamics of these mutant clones are shaped by complex interactions and regulatory mechanisms within the hematopoietic system. The lab team is exploring these dynamics for the early detection of harmful clones and the development of new treatment approaches.
Senescence tumor microenvironment in leukemia
Cellular senescence is a stress response mechanism that halts the proliferation of old, damaged or cancerous cells, with significant pathophysiological implications.
Senescent cells undergo phenotypic, genetic, epigenetic, nuclear and metabolic changes. A defining characteristic of senescence is the senescence-associated secretory phenotype, where senescent cells release bioactive molecules.
If these senescent cells aren't cleared, they can foster a proinflammatory and protumorigenic environment. The use of senolytic drugs to selectively eliminate senescent cells holds promise for controlling a range of age-related conditions and cancer.
The lab's main goal with this research is to better understand how stromal cells, particularly in the bone marrow, interact with and are influenced by blood cancer cells.
A recent discovery of cancer-associated fibroblasts derived from bone marrow mesenchymal cells in acute lymphoblastic leukemia offers a robust model to investigate the role of senescence in cancer-associated fibroblasts and its impact on the tumor microenvironment.
Reversing age-related changes in the hematopoietic compartment
Aging induces well-documented changes in the hematopoietic system that affect individual cell types and the surrounding microenvironment, including:
- Increased myeloid cell production.
- Rising numbers of phenotypically altered hematopoietic stem and progenitor cells.
- DNA damage.
- Clonal hematopoiesis within the hematopoietic stem cell compartment.
These changes heighten the risk of developing myeloid malignancies, although the link between hematopoietic stem cell heterogeneity and their transformation into leukemic stem cells remains unclear.
In addition, aging hematopoietic stem and progenitor cells show reduced autophagy activity and shifts in cellular metabolism. Age-related changes in the bone marrow niche further intensify the aging process within the hematopoietic system, creating a proinflammatory microenvironment.
Blood rejuvenation refers to processes or treatments aimed at revitalizing or restoring the function of blood to a more youthful or optimal state. This concept has garnered attention because of its potential to improve health, extend lifespan and combat age-related conditions.
Stem cells, particularly hematopoietic stem cells that give rise to all blood cells, play a critical role in maintaining a healthy blood system. Over time, the capacity of these stem cells to renew and differentiate declines, leading to less efficient blood function and immune system deficiencies.
Dr. Kirschner's team is investigating ways to rejuvenate or replace aging stem cells to restore youthful blood function. This research holds the potential to advance new treatments for aging-related conditions, including cardiovascular disease, neurodegeneration and immune system decline.