Why clonal hematopoiesis?

As we age, some of our blood stem cells can acquire mutations that causes them to expand resulting in the formation of their own distinct “clones”. This condition known as “clonal hematopoiesis” increases the chances of developing blood cancers such as leukemia. If we could identify and prevent such clones from expanding this can dramatically reduce risk for blood cancers. Despite its importance, we still don’t understand why these clones emerge only in some individuals and why only a small subset of such carriers’ eventually progresses to cancer?

Key Questions

1. Why blood stem cells undergo clonal changes and what are the underlying mechanisms?
2. How inherited genetic variants influence clonal hematopoiesis and blood cancers?
3. Does inherited genetic variants interact with cancer mutations?

Our Approach

1. Human Genetic Studies

We leverage human genetic studies to identify genetic risk variants underlying clonal hematopoiesis and myeloid malignancies. We prioritize variants from population-based genome-wide association studies (GWAS) and from studies on rare families with higher risk for these clonal disorders.

2. CRISPR/Cas9-Edited Blood Stem Cell Models

We model genetic risk variants into primary human hematopoietic stem and progenitor cells using CRISPR/Cas9 approaches and study their impact on stem cell function and clonal expansion. We are also interested in developing engineered mouse models for blood cancer predisposition.

3. Role of Enhancer Elements in Blood Cancer Risk

Majority of genetic risk variants identified from GWAS are non-coding and likely affect cell-type specific enhancer elements. We are very interested in mapping the enhancer-gene networks that are critical for blood cancer risk.

4. High-throughput screens

We are employing a variety of high throughput technologies to examine hundreds to thousands of genetic variants directly in primary human hematopoietic stem and progenitor cells (HSPCs).