Setting the Course: Consensus Research Priorities in MDS

The following is a summary of recommendations from the American Society of Hematology Workshop on Myelodysplastic Syndromes. 

Background

Myelodysplastic syndromes (MDS) include a spectrum of hematopoietic stem cell disorders characterized by dysplastic and ineffective blood cell production. Recent data from the Surveillance, Epidemiology, and End Results (SEER) and North American Association of Central Cancer Registries (NAACCR) databases estimate that approximately 15,000 people are diagnosed with MDS annually in the United States, with 80 percent of cases arising in people over the age of 60. Patients with MDS often have anemia that requires chronic blood product transfusions and are at a risk for mortality related to bone marrow failure and progression to acute myeloid leukemia (AML). Investigations to date have shown that the phenotype we recognize as MDS has varied biological and pathogenetic features.

The American Society of Hematology (ASH) represents more than 17,000 clinicians and scientists worldwide committed to the study and treatment of blood and blood-related diseases. The Society's members have been pioneers in the fields of bone marrow transplantation, gene therapy, and stem cell research. MDS represents an important disorder for scientific focus given its epidemiologic link to senescence, its significance as a pre-leukemia model, and its relevance to stem cell biology. With the graying of a large segment of the American population who are at emerging risk for these disorders, the advancement of research and treatment of MDS is one of the Society's priorities.

Hematology researchers are the scientific engine that will contribute to the accomplishments necessary to delineate pathogenetic features of the disease and are funded by the entire spectrum of National Institutes of Health (NIH) Institutes, including the National Heart, Lung, and Blood Institute (NHLBI), the National Cancer Institute (NCI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute on Aging (NIA); ASH and its members are appreciative of our long-standing collaboration with the Institutes and their support for the science driving new discoveries.

Over the course of discussions with ASH member experts in MDS and the directors at several NIH Institutes, ASH became increasingly concerned about the lack of any long-term programmatic funding at any of the Institutes specifically targeting MDS research. Consequently, ASH proposed hosting a research agenda-setting workshop to foster a dialogue about priorities and opportunities for research in MDS. Each of the Institutes expressed an interest in working with ASH - individually and together - to further explore the research needs for MDS.

The ASH Workshop on MDS took place on November 20, 2008, and was co-Chaired by D. Gary Gilliland, MD, Brigham and Women's Hospital, Harvard Medical School, Boston, MA¹ and Alan F. List, MD, Executive Vice President, Physician-in-Chief, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL. Participants² included noted scientists and clinicians in the area of MDS, including representatives from several institutes at NIH. The goals of the workshop were to assess what is already known and what is yet to be learned about MDS, prioritize research for this syndrome, and prepare a research agenda that would form the basis of a sustainable MDS research program at NIH. This document reflects ASH's recommendations and those of the workshop participants for MDS research, including priority areas, continued challenges, and a recommendation for the NIH to undertake a coordinated multi-institute approach to MDS, with NHLBI taking the lead.

Research Priorities

Three research areas were identified and prioritized by the workshop participants; they are listed below in rank order.

1. Determining the role of stem cell and hematopoietic senescence in MDS predisposition and pathogenesis.

• Epidemiologic data indicate that predisposition to MDS is age-dependent and is further modified by genotoxic exposures, supporting a link between the disease and hematopoietic stem cell senescence and/or the age-dependent accumulation of genetic abnormalities in hematopoietic stem cells.
• Heritable gene mutations affecting telomere maintenance illustrate the strong connection between replicative stem cell senescence, genomic instability, and a predisposition to MDS. While our understanding of the biology of stem cell senescence is limited, murine models and investigations in solid organ malignancies indicate that age-dependent changes in epigenetic control and patterns of microRNA expression may contribute to stem cell depletion and skewing toward myeloid commitment that merit further study in MDS. Structural and numerical chromosome abnormalities in MDS may reflect deregulation of genomic fidelity arising from acquired changes in the capacity for DNA repair.
• Numerous assays to investigate cellular senescence have emerged that can now be applied to MDS and normal hematopoietic stem cells including genetic, cellular protein, and humoral markers. Predisposition to MDS with age may also reflect interaction of the stem cell with age-dependent changes in the microenvironmental niche and immuno-senescence per se, both of which exert selective pressures external to the stem cell and its progeny.
• Emerging evidence from animal models suggests that the introduction of aged stem cells into a young recipient microenvironment restores replicative potential, emphasizing the importance of external cues in stem cell behavior.

2. Determining molecular genetics and epigenetics of MDS.

• MDS is a polygenic disease that will, therefore, benefit from genome-wide analysis for individual genes and genomic patterns that may be pathogenic or predictive of specific disease subtypes. Increasing evidence indicates that epigenetic abnormalities, including both global and gene-specific methylation, play a pathogenetic role in MDS based on data linking tumor suppressor gene inactivation with disease progression and the success of DNA methyltransferase (DNMT) inhibitors in treatment of the disease.
• Recent investigations indicate that only a small fraction of gene promoters are methylated in MDS, raising important questions as to cellular mechanisms directing gene selection, contributions of histone modifications such as acetylation and methylation, and other regulators of chromatin structure.
• Application of sensitive microarray technology such as single nucleotide polymorphism, gene expression, and microRNA arrays has shown that these innovative techniques can identify unrecognized sites of gene deregulation and gene expression signatures that have biological, prognostic, and potentially diagnostic significance.
• Better understanding of these processes will not only improve the diagnosis of MDS, but also provide additional targets for drug design and treatments for patients with MDS. It is expected that molecular profiling will lead to diagnostic and prognostic signatures and assist in understanding genetic predisposition (SNPs, mutations, etc.) to MDS.
• Novel, highly sensitive techniques, such as whole exome or genome sequencing, microRNA expression arrays, and genomic methylation tiling are priority platforms for molecular discovery to further molecular diagnostic and prognostic characterization, the understanding of the non-epigenetic and epigenetic effects of current therapeutics, and the understanding of the relationship of these processes to senescence, disease predisposition, and MDS stem cell biology.
• Transcriptional repression is believed to be an important contributor to ineffective hematopoiesis in lower risk disease; however, convincing laboratory data is lacking.
• Strategies that integrate the above technologies with assessment of transcriptional control should be prioritized to understand the interaction of molecular processes in disease behavior and the action of novel therapeutics.

3. Determining the roles of normal and cancer stem cells in MDS.

• Direct evidence supporting the presence of an MDS stem cell is lacking, reflecting the limitations of current assays.
• Recent work using highly purified murine and human hematopoietic stem cell (HSC) populations have identified stem cell gene expression signatures that can now be interrogated to identify disparities in gene regulation in MDS affecting self-renewal potential, competition with normal HSC, clonal expansion, and cell survival.
• Common convergence signaling pathways involved in terminal differentiation are altered in MDS, creating an opportunity for investigation of novel targeted therapeutics.
• In addition to the microenvironmental cues discussed earlier, insight into cellular control of sinusoidal trafficking and marrow egress of differentiated hematopoietic elements has created opportunities for investigation in MDS.
• Development of in vitro proxy assays for assessment of self-renewal is essential for testing new therapeutics.
• Animal models have proven valuable for candidate gene validation, and new murine models have greater relevance to human disease, creating opportunities for further understanding of disease biology and the actions of novel therapeutics.

Continuing Challenges of MDS Research

The workshop participants also identified continuing challenges in MDS research that need to be resolved in order to improve our understanding of the biology and pathogenesis of MDS, with the ultimate goal of improving therapeutic approaches to this disease. These include:

1. The lack of a central repository for normal (control) bone marrow specimens representing all decades of life (such as National Cooperative Tissue Network).
2. Small cell sample recovery necessitating utilization of limited cell technology.
3. Identification of preferred cell population for analysis.
4. Variable collection/processing/cryopreservation approaches and quality (i.e., need for standardized best practices in these areas).
5. Inadequate stem cell assays/models.
6. Limited relevance and applicability of animal models of MDS.

Recommendations

One of the major challenges for MDS research is the lack of a "home" for it within NIH. Because MDS is such a heterogeneous disease, many Institutes, depending on their research affinities, could possibly "house" MDS. For example, the role of natural aging processes in MDS might be well-suited for study within the context of NIA, while topics that may be of interest to NHLBI, NIDDK, or NCI run the gamut of studies investigating transcriptional dysregulation of hematopoietic cell differentiation in MDS, defects in mature cell function in patients with MDS, or progression from MDS to AML. However, there has not been a concentrated effort from any of the Institutes in recent years to tackle MDS; instead each Institute has been releasing a limiting few RFAs on MDS each year, resulting in growing concern of MDS "falling through the cracks." The following are ASH's recommendations that address this pressing need:

1. A multi-center, comprehensive, and sustainable program for MDS research should be developed within NIH. Based on its history, its mission, and expressed interest, NHLBI stands out as an Institute that should take the lead in this area.
2. Funding mechanisms should be developed in a way to be applicable to any institute with emphasis on integrative strategies.
3. Emphasis should be placed on rapid request for applications (RFAs) for ancillary studies in clinical trials for interim directives.

Summary

The prevalence of MDS is increasing in the United States. This increasingly common and often fatal bone marrow failure disorder primarily affects individuals over 60 years of age and individuals who have undergone chemotherapy and/or radiation therapy for previous treatment of cancer. Consequently, a sustainable research program into the causes of this disorder and the development of effective treatments is critically needed. In 2008, a panel of experts brought together by the American Society of Hematology, in collaboration with several NIH Institutes, recommended a research agenda for MDS. ASH urges NHLBI, working with NCI, NIDDK, and NIA, to develop a plan to implement a coordinated MDS research agenda.

1. As of February 2009, Senior Vice President of Merck Research Laboratories and Head of Oncology Franchise at Merck, Co., Whitehouse Station, NJ
   
   
2. Peter Aplan, MD, NCI; Nancy Berliner, MD, Brigham and Women's Hospital; Terry Rogers Bishop, PhD, NIDDK, NIH; Charles P. Clayton , Association of Specialty Professors (ASP); Nancy DiFronzo, PhD, NHLBI, NIH; Benjamin L. Ebert, MD, Dphil, Brigham and Women's Hospital; Margaret Goodell, PhD, Baylor College of Medicine; Steve Gore, MD, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University; Catriona Jamieson, MD, PhD, Moores Cancer Center, UC San Diego; Peter Lansdorp, MD, PhD, Terry Fox Laboratory, BC Cancer Research Centre; Dan L. Longo, MD, NIA, NIH; Jar Maciejewski, MD, PhD, Taussig Cancer Center, Cleveland Clinic; Ari Melnick, MD, Weill Cornell Medical College; William Merritt, PhD, NCI, NIH; R. Allan Mufson, PhD, NCI, NIH; Susan Nayfield, MD, MSc, NIA, NIH; Stephen Nimer, MD, MemorialSloan-Kettering Cancer Center; John Thomas, PhD, NHLBI, NIH; Dan Wright, NIDDK, NIH; Neal Young, MD, NHLBI, NIH.