Questions Underlying the Pathophysiology of MDS and Therapy
Executive Summary from an NHLBI Working Group
September 7-8, 2011
The National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI) co-sponsored the NIH State of the Science Symposium on the Myelodysplastic Syndromes (MDS) in Bethesda, Maryland on Sept 7th and 8th, 2011. Immediately following the Symposium, the Division of Blood Diseases and Resources of NHLBI convened a Working Group of scientific and clinical investigators to discuss the research needed to advance our understanding of MDS.
MDS are a heterogeneous group of bone marrow stem cell disorders characterized by ineffective hematopoiesis leading to blood cytopenias, and by a high incidence of transformation to acute myeloid leukemia (AML). MDS occurs most frequently in the elderly, with a median age at diagnosis of 65 years, and an incidence reaching 35 to 40/100,000/year above the age of 65. As the median age of the US population increases, the impact on the healthcare system is expected to escalate.
The biological heterogeneity in patients with low-risk and high-risk disease have made it difficult to decipher the pathophysiological mechanisms that contribute to MDS. Recently, however, high throughput genomic techniques have identified several genetic and epigenetic mechanisms thought to be involved in the etiology of MDS, including the most frequent MDS-associated cytogenetic abnormality (5q deletion) and genes encoding proteins controlling DNA methylation, chromatin conformation, and pre-mRNA splicing. Murine models are beginning increase our understanding of the multistep nature of MDS pathogenesis and the potential role of the microenvironment. Additionally, genetic analyses have revealed some of the mechanisms underlying familial disorders associated with MDS, while epidemiological studies have identified causal exogenous factors in 15 to 20% of MDS.
Most MDS patients suffer from the accumulating consequences of marrow failure or other age-related diseases, and nearly 30% develop acute myeloid leukemia. The existing treatments, including growth factors, DNA methyltransferase inhibitors (azacitidine and decitabine), lenalidomide, and allogeneic stem cell transplantation, are not optimal. For the vast majority of patients, treatments are not curative. As a result, the median survival of a 65 year old patient with MDS is 2-to-3 years, which is less than 20% of the expected survival of healthy 65 year old men (17 years) and women (20 years) in the US. Clearly improved therapies are needed urgently.
Likewise, to improve therapeutic outcomes, a more complete understanding of the etiology and pathogenesis of MDS is needed. It is critical to understand 1) how hematopoiesis differs from normal in patients with MDS and in the elderly; 2) the role of the microenvironment in MDS pathogenesis; 3) the genetic basis associated with other common MDS-associated cytogenetic abnormalities (including -7, del 20q, +8) and with multistage pathogenesis; 4) how inherited predisposing and exogenous factors can lead to MDS; and 5) the relationship between genetic mechanisms, MDS hematopoietic stem cells, ineffective hematopoiesis, epigenetic abnormalities, and progression to AML. Importantly, it will be important to identify targets for future therapies and to determine the exact mechanisms of action of currently available drug therapies, as well as mechanisms of relapse.
The NHLBI Working Group identified key scientific questions that must be addressed to further our understanding of MDS and to facilitate implementing novel and effective therapies. The scientific questions were not prioritized, but clustered within the following five categories: discovery; mechanisms and functional biology; aging and clonality; translation; and target identification and therapeutic development.
- Several genomic and epigenomic abnormalities have been identified in MDS patients; what screening procedures are needed to determine others, and can these be utilized therapeutically?
- Which factors associated with inherited MDS are also seen in acquired MDS? How do the factors associated with inherited MDS inform us about acquired MDS?
- What is the role of the innate immune system in MDS, and can this be modulated for therapeutic benefit?
- Does the pro-inflammatory microenvironment contribute to the transformation of MDS to AML, and if so how?
- What roles do protein translational pathways play in the anemia seen in low risk MDS, specifically in non del 5q?
- What are the “founder mutations” in MDS that drive initiation and evolution, and what are the molecular mechanisms for this?
- What is the molecular basis for programming hematopoietic stem cells (HSCs) in the MDS phenotype?
- What is the molecular basis for the aberrant methylation state in the MDS phenotype?
- Are HSC and hematopoietic progenitor cells (HPCs) without chromosomal and molecular abnormalities that are found in patients with MDS truly normal? Do these HSCs/HPCs respond to cytokines and/or the microenvironment in the same way as cells from normal donors?
- Is MDS a stem and/or progenitor cell defect? Does progression to overt leukemia or to a hypocellular/aplastic state result from defects in stem vs. progenitor cells?
II. Mechanisms and Functional Biology
- What is the molecular signature of HSCs or HPCs in MDS?
- How can normal hematopoiesis be stimulated in patients with MDS?
- How do candidate genes (i.e. splicing factor mutants or other mutants) contribute to ineffective hematopoiesis and MDS evolution and biology?
- What drives the dominance of del 5q and other chromosome/molecular abnormalities in MDS?
III. Aging and Clonality
- Are the phenotypic and functional integrity of HSCs and HPCs in MDS patients the same as in age-matched controls? Which changes in MDS HSCs are uniquely different from normal aging HSCs, and do these changes underlie the mechanisms that suppress normal polyclonal hematopoiesis?
- How do the normal and MDS HSC and HPC compartments evolve with disease progression and or therapy (i.e. DNA methyltransferase inhibitor treatment)?
- What is the extent of clonality in MDS at different stages?
- Is the bone marrow microenvironment (stroma) abnormal in MDS patients? How does normal and possibly abnormal stromal contribute to induction and/or progression of MDS?
- What is the biological/molecular basis of response to DNA methyltransferase inhibitors and epigenetic modifiers?
- What biomarkers predict prognosis or therapeutic response and can these be validated?
- How can we accurately distinguish low-risk from high-risk patients? What treatments are most efficacious for each group, and can these approaches be optimized? Can we improve patient selection and outcomes following allogeneic hematopoietic stem cell transplantation?
V. Target Identification and Therapeutic Development
- What are the new drug targets in MDS? Can new drug targets be derived from mechanistic insights into the molecular and cellular basis of MDS?
- Can cell lines and better murine models suited for studies of MDS pathophysiology be developed and used for testing new therapeutics ex vivo?
Working Group report on the NHLBI website; Summary of Symposium to be published a scientific journal.
In addition to the program officials from the NHLBI, the meeting was attended by staff from the NCI, NIDDK, and the VA.
Working Group Members:
Hal Broxmeyer, PhD (co-Chair), Indiana University School of Medicine
Pierre Fenaux, MD, PhD (co-Chair), Hospital Avicenne, University Paris 13
Peter D. Aplan, MD, National Cancer Institute (NCI)
Nancy Berliner, MD, Brigham and Women's Hospital
Monica Bessler, MD, PhD, The Children’s Hospital of Philadelphia
Benjamin Ebert, MD, PhD, Harvard University
Eva Hellström-Lindberg, MD, PhD, Karolinska Institutet, Stockholm
Guillermo Garcia-Manero, MD, MD Anderson Cancer Center
Steven D. Gore, MD, Johns Hopkins University
Timothy Graubert, MD, Washington University School of Medicine
James G. Herman, MD, Johns Hopkins University
Marshall S. Horwitz, MD, PhD, University of Washington School of Medicine
Sten Eirik W. Jacobsen, MD, PhD, University of Oxford
Jaroslaw P. Maciejewski, MD, Ph.D, Cleveland Clinic Lerner College of Medicine
Ari M. Melnick, MD, Weill Cornell Medical College
Stephen D. Nimer, MD, Memorial Sloan-Kettering
Yogen Saunthararajah, MD, University of Illinois at Chicago Taussig Cancer Institute
David Scadden, MD, Harvard Stem Cell Institute
Daniel Starczynowski, PhD, Cincinnati Children's Hospital Medical Center
David P. Steensma, MD, FACP, Dana-Farber Cancer Institute
Amit Verma, MD, Albert Einstein College of Medicine Cancer Center
Mathew J. Walter, MD, Washington University
Cheryl Willman, MD, University of New Mexico Cancer Center
Joao L. Ascensao, MD, PhD, Department of Veterans Affairs
Terry R. Bishop, PhD, National Institute of Diabetes & Digestive Kidney Diseases (NIDDK), NIH
Nancy L. DiFronzo, PhD, NHLBI, NIH
Basil A. Eldadah, MD, PhD, National Institute on Aging, NIH
Manjit Hanspal, PhD, NHLBI, NIH
W. Keith Hoots, MD, Director DBDR, NHLBI, NIH
William D. Merritt, PhD, NCI, NIH
Robert A. Mufson, PhD, NCI, NIH
Lynn Sorbara, PhD, NCI, NIH
Daniel Wright, MD, NIDDK, NIH
Alan F. List, MD, Moffit Cancer Center.
Nancy DiFronzo, PhD. NHLBI, NIH
Manjit Hanspal, PhD. NHLBI, NIH
Last Updated November 2011