Understanding Dr. Agarwal’s RUNX1-FPD Research Article Published in a Top-Tier Medical Journal

By Dr. Katrin Ericson

Click here to see the original article: “New Insights on Targeting CD74 Signaling for RUNX1-FPD Therapies”

Insights for the Patient Community

Key Points

• Inflammation in the bone marrow is an early event in RUNX1-FPD and plays a major role in driving blood cancer development.

• Existing drugs, such as sirolimus (an mTORC1 inhibitor), show promise in reducing inflammation in RUNX1-FPD.

• This research led to the launch of a clinical trial testing sirolimus in RUNX1-FPD patients.

• The research team identified CD74, a protein found on the surface of blood cells, is higher in RUNX1-FPD. CD74 is closely linked to inflammation (and elevated levels of mTORC1). CD74 may be both a target for future treatments and a warning sign of blood cancer risk.

Background and Research Project Plan

Patients with RUNX1-FPD have a much higher risk of developing blood cancers, primarily acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). This increased risk stems from the precancerous state created by inherited mutations (DNA spelling changes) in the RUNX1 gene. 

Dr. Anupriya Agarwal, a professor at Oregon Health & Science University, is dedicated to uncovering what defines this precancerous state to develop interventions that could prevent blood cancer development in RUNX1-FPD patients.

Several years ago, Dr. Agarwal and her colleagues proposed that inherited RUNX1 mutations increase the risk of blood cancers by promoting chronic inflammation in the bone marrow (the central hub of the blood system, where all blood cell types are continuously generated throughout life). Her earlier work demonstrated that blood cancer cells in AML thrive in an inflamed bone marrow environment, while healthy blood cells do not. This finding suggested that if they could reduce inflammation, they might be able to slow or stop cancer from developing.  

To test this theory, Dr. Agarwal collaborated closely with Dr. Paul Liu and his team at the NIH, who run the RUNX1-FPD Clinical Research Study. Dr. Liu generously provided rare and precious bone marrow and blood samples from patients participating in the study. These samples formed the foundation of the research.

Dr. Mona Mohammadasseini, a postdoctoral researcher in Dr. Agarwal’s laboratory, led the project and conducted most of the experiments. Her research focused on confirming whether inflammation is indeed present in the bone marrow of RUNX1-FPD patients and whether suppressing it could provide therapeutic benefits. For five years, the team conducted a series of extensive experiments, which are detailed in the recent publication.

This ambitious project was made possible through the support of RRP, Alex’s Lemonade Foundation, and Edward P. Evans Foundation.

Research Results

The research uncovered significant abnormalities in the blood cells within the bone marrow of RUNX1-FPD patients. The team found that blood stem cells (specialized cells capable of producing all types of blood cells; scientifically referred to as hematopoietic stem and progenitor cells or HSPCs) are biased toward developing into myeloid cells, a type of white blood cell. This occurs at the expense of producing other essential cell types, particularly platelets.

It’s important to note that the most common type of blood cancer in RUNX1-FPD patients is acute myeloid leukemia (AML), a cancer that originates from myeloid cells. The overproduction of myeloid cells is a warning sign of an imbalance in the blood system that can pave the way for “myeloid” blood cancers like AML. Researchers found that this imbalance is caused by the overactivation of specific survival and inflammatory pathways within the blood stem cells.

The Agarwal team also discovered that the bone marrow environment (the tissue surrounding the blood stem cells) in RUNX1-FPD patients contains abnormally high levels of cytokines. These small proteins play a key role in driving inflammation. This chronic inflammatory stress alters the behavior of the blood stem cells, pushing them to produce more myeloid cells.

One of the team’s most important findings was the identification of CD74, a protein that is highly active in the blood stem cells of RUNX1-FPD patients, even before leukemia develops. CD74 triggers inflammatory pathways, including mTOR and JAK/STAT, which further increase cytokine production and drive disease progression. This creates a self-reinforcing cycle where inflammation feeds on itself, worsening the imbalance in the bone marrow over time.

CD74, a protein that is highly active in the blood stem cells of RUNX1-FPD patients, triggers inflammatory pathways, including mTOR and JAK/STAT, which further increase cytokine production and drive disease progression.

Sirolimus and ruxolitinib were shown to reduce inflammation and restore normal blood cell development in both laboratory studies and animal experiments, offering hope for potential therapeutic strategies.

Importantly, the team demonstrated that blocking CD74 signaling with a chemical compound called ISO-1 can help correct the abnormalities seen in RUNX1-FPD. However, since no CD74-specific medicines are currently available, the researchers turned their attention to other drugs that target proteins within the CD74 signaling network. Note that ISO-1 could not be used because it is only a laboratory-grade chemical compound, not fit for human medicinal use.

They identified two promising options: sirolimus, which inhibits mTORC1, and ruxolitinib, which inhibits JAK/STAT pathways. Encouragingly, experiments showed that both sirolimus and ruxolitinib were able to reverse the abnormal blood cell differentiation seen in RUNX1-FPD cells and mouse models. These medicines reduced inflammation and restored normal blood cell development in both laboratory studies and animal experiments, offering hope for potential therapeutic strategies.

The research also highlighted the role of inflammatory cytokines such as TNF-α, IL-1β, and CXCL-8, which contribute to a harmful bone marrow environment in RUNX1-FPD patients. These cytokines exacerbate the blood cell defects, creating an environment that favors blood cancer development.

The research team showed that CD74 drives inflammation by activating key molecular pathways, including PI3K, mTOR, and JAK1/2. These pathways regulate critical processes such as cell proliferation, survival, and the release of inflammatory cytokines. Together, these findings strengthen the case for targeting CD74 and its downstream signaling as a promising therapeutic strategy for RUNX1-FPD.

Implications for Patients

This research offers hope for patients with RUNX1-FPD by identifying potential strategies to prevent the progression of the disease to blood cancer. Chronic inflammation is a pivotal driver of disease progression, and addressing it through targeted therapies could significantly improve patient outcomes. 

Why This Research Matters

This research project led directly to the launch of the ongoing sirolimus pilot study, which is now open to patients. Based on guidance from our Scientific Advisory Board and input from several patient advisors, sirolimus was prioritized over ruxolitinib as the first medicine to investigate in a clinical trial, largely due to its well-established safety profile.

Additionally, the Agarwal team's findings highlight the need for further clinical development of CD74 inhibitors, which show great promise as a potential intervention.

What’s Next for Patients?

Patients can play a critical role in advancing research by staying informed, participating in clinical studies like the new sirolimus pilot study or the ongoing NIH natural history study, and advocating for increased awareness and funding for RUNX1-FPD research. Sharing experiences and contributing to the RUNX1 Patient Data Hub can provide invaluable data to guide future studies.

By fostering collaboration between researchers, clinicians, and the patient community, we can move closer to improving outcomes for all those affected by RUNX1-FPD.