Research Projects Funded

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Following is a research summary of our grant program awardees. Below is a brief introduction to the principal investigator and the primary topic of research. We are fortunate to have such a strong, diverse selection of renown researchers as partners.

RUNX1-ALSF (Alex’s Lemonade Stand Foundation) 2018 Grant Awardees

Marc Raaijmakers, MD, PhD, Professor of Hematology, Erasmus MC Cancer Institute in Rotterdam, the Netherlands. Dr. Raaijmakers aims to uncover whether RUNX1-FPD patients may be at heightened risk of blood cancer because of an unhealthy blood stem cell niche, which is the bone marrow. Blood stem cells are responsible for generating our blood each and every day. They are also the cells that are responsible for driving leukemia when they acquire mutations in specific genes. Therefore, blood stem cells are incredibly important to our survival and must be protected from any undo stress that may result in dangerous mutations. The bone marrow, where blood stem cells live, provides a highly specialized environment that protects the stem cells. Dr. Raaijmakers is an expert on the bone marrow blood stem cell niche. In his research proposal he outlines a series of experiments that aim to test whether a bone marrow niche that has lower levels of RUNX1 activity, like in RUNX1-FPD patients, is a key contributing factor in the progression to leukemia. His work may provide a proof-of-concept that therapeutically targeting the bone marrow niche is a rational approach to preventing leukemia.

RUNX1-LLS (Leukemia and Lymphoma Society) 2017 Grant Awardees

Dr. Guy Sauvageau, University of Montreal, Canada, ‘RUNX1 mutations that confer exquisite sensitivity to glucocorticoids’. Dr. Sauvageau discovered that a class of steroid hormones called glucocorticoids selectively inhibits the growth of acute myeloid leukemia (AML) cells containing RUNX1 mutations in cell culture. He plans to determine how glucocorticoids inhibit the growth of RUNX1 mutant AML cells, and to test the ability of glucocorticoids to inhibit AML in a mouse model.

Dr. Benjamin Ebert, Harvard Medical School, USA, ‘Interaction of RUNX1 and the cohesin complex in megakaryocyte development and myeloid disease’. Dr. Ebert will study the cooperation between mutations in RUNX1 and in a gene encoding a member of the cohesin complex, STAG2. He plans to generate a mouse model for the combined RUNX1 and STAG2 mutations and study hematopoiesis and leukemia progression. He will also evaluate inhibitors of CDK8, a member of the transcriptional mediator complex, for their activity and mechanism of action in the context of RUNX1 and/or STAG2 mutations.

Dr. Stephen Nimer, University of Miami – Miller School of Medicine, USA, ‘Epigenetic-modifying enzymes in RUNX1-FPD’. Dr. Nimer will evaluate the ability of inhibitors or activators of epigenetic gene regulation to promote the differentiation, or inhibit the self-renewal, proliferation, and survival of RUNX1 mutant hematopoietic cells derived from cultures of human-induced pluripotent stem cells (iPSCs). He will also generate a mouse model with combined mutations in RUNX1 and in a gene called ASXL1, which have been found to co-occur in a subset of RUNX1-FPD patients with AML, and test the activity of inhibitors or activators of epigenetic gene regulation in this model.

RUNX1-ALSF (Alex’s Lemonade Stand Foundation) 2017 Grant Awardees

In November of 2017 we awarded the second cycle of our joint grant program with ALSF.  Awards are for $250,000 for research leading to the prevention of the transition from pre-leukemia to leukemia for patients with RUNX1-FPD.  This cycle we awarded two grants.  Following is a brief description of each project under the leading researcher.

Dr. Mortimer Poncz, Children’s Hospital of Philadelphia (CHOP), ‘Drug Screen for FPD/AML Therapeutics’.  Dr. Poncz and his team propose to enhance RUNX1 levels with the target of correcting the platelet problem, expecting that correction will also correct the risk of getting leukemia. The group specializes in studies on how to make platelets from megakaryocytes and have already identified one drug called RepSox that can correct many of the megakaryocyte defects seen in FPD cells.  They will continue studies with RepSox and also do a screening of drugs looking for other compounds that correct FPD megakaryocytes at doses that an individual might be able to take on a long-term basis.  Drugs will also be tested in RUNX1-deficient mice, adjusting candidate drugs to the lowest level that corrects the platelet counts in these mice.  The longer-term goal is to test whether that dose protects the mice from getting leukemia.  The lab envisions applying this strategy to affected individuals who will take the drug at the lowest dose that corrects their platelet count, with the expectation that the dose will also protect the individual from AML with little side-effects.  They believe that the proposed strategy offers a short-track for drug identification that both reduces the risk of bleeding and of developing AML.

Dr. Anupriya Agarwal, Oregon Health & Science University (OHSU), ‘Role of Inflammatory Microenvironment in Clonal Evolution and Progression from FPD to AML’.  Dr. Agarwal has performed genetic sequencing and identified 16 patients with AML who have inherited RUNX1 mutations as well as additional mutations in known cancer-causing genes.  The lab proposes to study how RUNX1 mutations create a “pre-leukemic” environment, to identify which inflammation-causing cytokines present in this “pre-leukemic” environment, and to determine which of these cytokines can then contribute to disease progression and to full-blown leukemia.  The lab has found that samples from the 16 patients were sensitive to certain drugs, and this information will be used to help identify new treatment strategies for these patients. The knowledge gained in this study will help determine effective treatments to prevent FPD from transforming to AML, leading to improved outcomes for patients with FPD.  In the long term, information gained from the study will be used to discover how to predict which people with FPD will develop AML and how best to monitor families with the RUNX1 mutation for early detection of AML, thereby expanding our database of FPD patients and families.  This will also allow for the design of clinical trials to be aimed at early intervention in these patients.

RUNX1-ALSF (Alex’s Lemonade Stand Foundation) 2016 Grant Awardees

Dr. Ravi Majeti, Stanford University, ‘Characterization of Pre-Leukemia Associated with Familial RUNX1 Mutations’. Dr. Majeti and his team propose to investigate the disease pathogenesis and pre-leukemia by determining the effects of familial RUNX1 mutations on hematopoietic stem and progenitor cells using CRISPR methods and a mouse host model. Additionally, they aim to determine the contributions of familial RUNX1 mutations in HSPCs and the bone marrow microenvironment to aberrant pre-leukemic hematopoiesis.

Dr. Alan B. Cantor, Boston Children’s Hospital, ‘Pharmacologic Enhancement of Residual Wild Type RUNX1 Protein Activity in RUNX1-FPD’. Dr. Cantor will investigate whether enhancing the residual wild type RUNX1 protein by pharmacologic means is able to reduce the chances of progression to MDS/ leukemia as well as improve the platelet function of the disorder. The hope is to understand RUNX1 regulation in order to develop therapies for RUNX1-related hematologic malignancies. By using pluripotent (iPSC) cell lines from RUNX1-FPD patients and an in-vivo mouse model, the research aims to establish the extent to which SFK inhibitors enhance total RUNX1 activity as well as to establish a high throughput assay for RUNX1 transcriptional activity and screen about 100,000 compounds for additional enhancers.

Dr. Eirini Papapetrou, Icahn School of Medicine at Mount Sinai, ‘Identifying Therapeutic Targets to Prevent Progression of Familial RUNX1 Disorder to AML using Novel iPSC Models’. Papapetrou’s lab aims to develop an iPSC-based model of progression of familial RUNX1 disorder with the goal of identifying therapeutic targets to prevent leukemia progression.

Dr. Marshall S. Horwitz, University of Washington, ‘Restoring RUNX1 Levels in RUNX1-FPD’. Dr. Horwitz’s research aims to inhibit the degradation of the wild-type RUNX1 protein through the ubiquitin-proteasome pathway by evaluating drugs currently in use or undergoing clinical trials in other forms of cancer. Additionally, his research will attempt to boost RUNX1 expression to reset its auto-regulatory circuit. Studies will be performed using patient-derived iPSC.

Dr. Leonard I. Zon, Boston Children’s Hospital, ‘Modeling RUNX1-associated Clonal Hematopoietic Disorders in Zebrafish’. Dr. Zon will use his ‘famous’ zebrafish program to model RUNX1-FPD to study and understand the combination of secondary mutations to understand disease pathogenesis. This would allow for early recognition in order to reverse abnormally mutated clonal expansion and restore normal hematopoiesis.

RUNX1 Research Program Independent Grants

Dr. Anna Brown and Prof. Hamish Scott, Centre for Cancer Biology at the University of South Australia and SA Pathology, ‘RUNX1 FPD Mutation Database’.

We are pleased to announce that we have awarded a one-year, $90,500 grant to Dr. Anna Brown and Professor Hamish Scott of the Centre for Cancer Biology at the University of South Australia and SA Pathology for this very purpose, in their creation of an ‘RUNX1 FPD Mutation Database’. Dr. Brown and Dr. Scott will present an update on the database at our November scientific meeting. Following is a description of the project:

Recent advances in genetic sequencing technology applied by many RUNX1-FPD research groups around the world have highlighted their value in understanding the somatic genetic changes that are associated with the development of malignancies in germline RUNX1 mutation carriers. Collectively, this information can lead to powerful insights that are essential in order to apply precision-medicine based diagnosis, risk assessment, monitoring, and therapeutic intervention. Dr. Brown, Prof. Scott and the team at the Centre for Cancer Biology in Adelaide are leading a project to generate a data-sharing platform for investigators to contribute germline and somatic genomic sequence data from germline RUNX1-mutated individuals. The aim is to use genomics analysis software developed at the Centre for Cancer Biology to create a custom-designed web portal for RUNX1 genomics data. This will allow investigators from around the world to deposit data in a central location where it can be viewed and queried as a single cohort. Generating a RUNX1 world genomics cohort through data aggregation will allow significant genetic and biological questions to be asked and answered, providing a resource that will continue to grow with ongoing sequencing efforts.

Dr. Nancy A. Speck, University of Pennsylvania, ‘Mouse Models of Secondary Mutations in RUNX1-FPD

We have awarded a three year, $600,000 grant to our Scientific Director, Dr. Nancy A. Speck, for a research project entitled ‘Mouse Models of Secondary Mutations in RUNX1-FPD”.  Dr. Speck is developing a mouse model of RUNX1-FPD by introducing mutations into the RUNX1 gene that lower the effective RUNX1 dosage in the mouse.  She proposes to use this model to test which secondary mutations found in MDS and AML are the most potent at driving clonal hematopoietic stem cell expansion and leukemia in the context of lower levels of RUNX1.  This study will complement the planned longitudinal sequencing study of secondary mutations in RUNX1-FPD patients that the RRP is planning to launch in the near future, and also the efforts by Dr. Zon’s and Dr. Majeti’s laboratories to develop human xenograft and zebrafish models.  Knowing which acquired mutations behave most aggressively to promote hematopoietic stem cell expansion and leukemia will help physicians decide how early to intervene if a patient has evidence of clonal hematopoiesis.  The RUNX1-FPD mouse model will be made available to other investigators who wish to test the activity of drugs to delay, prevent, or reverse clonal hematopoietic stem cell expansion associated with acquired mutations.

Zuzana Tothova, MD, PhD, Dana-Farber Cancer Institute, Instructor in Medicine at Harvard Medical School, Associate Member of the Broad Institute, and principal faculty in the Harvard Stem Cell Institute

The RUNX1 gene encodes a protein that falls into a specific category of proteins called transcription factors. Transcription factors are proteins that can control the output of protein production from other genes. Transcription factors are analogous to a hand turning a light switch on or off, where the switch represents the control of many genes. RUNX1 is a critical transcription factor for blood cells. Yet RUNX1 cannot exert its function of turning on or off different genes in the blood without its specific protein partners. When RUNX1 and its partners form a complex, only then will the on or off switch controlling other genes work.

In diseases, like RUNX1-FPD where a transcription factor is not working at 100% capacity or is in some way dysfunctional, some blood cells attempt to adapt and compensate for the deficiency and this adaptation can lead to cancer. Dr. Tothova and colleagues have found that in both acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), cells with mutations in RUNX1 often also have mutations in a gene called STAG2. This second mutation in STAG2 is evidence of an adaptation made by the cells. STAG2 is a protein involved in gene activation because of its key role in controlling the architecture of DNA. Dr. Tothova’s research is focused on understanding why mutations in STAG2 help diseased blood cells survive and expand. She is doing this by evaluating liquid-liquid phase separation condensates in healthy blood cells versus RUNX1-FPD blood cells. Liquid-liquid phase separation was only very recently described as a new model of gene control. This model suggests that the areas in which gene control is occurring, within the core of the cell (the nucleus), are physically distinct and form structures like water droplets in order to compartmentalize these critical cellular reactions. Dr. Tothova hypothesizes that the liquid phase condensates, the water droplets, in RUNX1-FPD blood cells are reorganized. Her research aims to uncover a new therapeutic strategy that would specifically target mutant phase condensates in RUNX1-FPD blood cells that are transforming into cancer cells, potentially stopping cancer formation in its tracks.