The Erdheim-Chester Disease Global Alliance (ECDGA) is honored to support forward-thinking research that helps unravel the mysteries behind Erdheim-Chester Disease (ECD). One of our most compelling funded projects, awarded in 2023 with a two-year, $200,000 research grant, is led by Dr. Matthew Collin in collaboration with Dr. Jyoti Nangalia and Dr. Eli Diamond. Their study, “Inferring the Origin of Erdheim-Chester Disease from Phylogenetic Mapping,” is offering new insights into some of the most common and deeply personal questions patients ask: Where did my disease come from? How long have I had it? Could it have been caught earlier?

This ambitious research project seeks to do more than understand ECD—it aims to trace it back to its earliest moments in a person’s life.

What Is Phylogenetic Mapping?

At the heart of this study is a technique called phylogenetic mapping, which is essentially the construction of a “family tree” of blood stem cells. The process involves growing single stem cells from a patient’s bone marrow in the lab, sequencing their entire genomes, and then identifying subtle DNA differences between them. These small variations allow researchers to reconstruct the cell’s lineage and timeline, pinpointing when specific mutations—like the ones that cause ECD—occurred.

This approach gives scientists the ability to “date-stamp” the ECD-causing mutations and estimate how long those mutations remained dormant before progressing into disease. It also allows them to explore whether additional mutations helped the disease evolve and which biological factors influenced this evolution over time.

Early Findings: Tracing ECD Over Decades

So far, Dr. Collin and Dr Nangalia’s team have studied two patients with high-risk, multisystem ECD/LCH. Their findings show that in both cases, the mutation responsible for ECD likely originated over a decade before symptoms began. Both patients had multiple simultaneous mutations in key genes such as KRAS, NRAS, and BRAF, all occurring on separate branches of their phylogenetic trees. Interestingly, all of this unfolded on a background of bi-allelic TET2 mutations, which developed much earlier in life.

These early results suggest that ECD, while rare, may develop over many decades in a way similar to myeloproliferative neoplasms, which are far more common blood cancers. This finding not only enhances our understanding of ECD but also bridges its biology with other well-known hematologic conditions.

Understanding Disease Progression

The project aims to answer three core questions:

1. When do ECD-driving mutations occur, and how long do they take to cause disease?
   – Preliminary findings indicate that significant mutations can lie dormant for years or even decades before symptoms arise.

2. How do mutations like BRAFV600E interact with earlier genetic changes like TET2?
   – The team found that mutations in the MAPK pathway occurred within TET2-mutated clones, but each operated independently—challenging previous assumptions.

3. Are there new, undiscovered mutations that contribute to ECD in patients without known genetic changes?
   – While no new driver mutations have been identified yet, the research is ongoing.

Overcoming Challenges and Next Steps

One challenge the team faces is studying patients with lower-risk disease. In these individuals, the presence of disease-causing mutations in blood or bone marrow is too sparse to grow usable stem cell clones. However, alternative strategies such as primary template amplification are being explored, though sequencing errors remain a technical hurdle.

In the final phase of the project, Dr. Collin’s team will complete their data analysis, submit abstracts to major scientific meetings (including EHA and the ECDGA symposium), and publish their findings. The goal is to show how ECD emerges through a slow, unique evolutionary process tied to genetic changes that may begin decades before symptoms appear.

Why This Research Matters

By tracing the biological history of ECD, this study could open the door to earlier detection, personalized treatment planning, and even a better understanding of why certain organs are affected in different patients. The insights gained could also help clinicians recognize that although ECD is rare, it shares genetic pathways with more common cancers, which may accelerate diagnosis and treatment through broader clinical awareness.

At ECDGA, we believe in funding science that transforms lives. This groundbreaking work is only possible through the dedication of researchers like Dr. Collin and the support of our donors and global community.

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The Erdheim-Chester Disease Global Alliance (ECDGA) does not provide medical advice, diagnoses, or treatments. All content is for informational purposes only. Please consult with a healthcare provider for medical concerns.