ASH 2012 - Reviewing MDS Progress from Research and Clinical Perspectives | Aplastic Anemia and MDS International Foundation

ASH 2012 - Reviewing MDS Progress from Research and Clinical Perspectives

Dr. Graubert is an associate professor in the Department of Medicine, Oncology Division at the  Washington University School of Medicine in St. Louis, Missouri. Here, he speaks about developments in genetic studies in MDS research presented at the December 2012 American Society of Hematology (ASH) Annual Meeting that hold promise for eventual new approaches to drug therapy and treatment.

We hear that there is increasing interest and research in the role that genes and genetic mutations have in affecting the course of MDS. Were there any studies of particular significance in this area?

Yes, there is a lot of activity in the area of MDS genetics. The general goals of these studies are to use genetics to develop better ways of diagnosing MDS, to predict which patients will have a better outcome versus those with more aggressive disease, and which patients might benefit most from existing therapies. Identifying new therapeutic approaches and learning more about the basic biology of the disease are additional goals. Several groups of researchers are now screening large numbers of genes known to be recurrently mutated in MDS in large patient cohorts to determine how often these genes are mutated in MDS bone marrow samples. The goal is to define patterns of mutations that tend to co-occur in the same samples (suggesting that these mutations work together to cause MDS) and to determine the impact of mutations in these genes on prognosis.

One study that is representative of this kind of work was presented in the “late breaking abstract” session on the last day of the meeting (Papaemmanuil, et al). This group of European investigators is part of the International Cancer Genome Consortium, Chronic Myeloid Disorders Working Group. In their research, they selected 111 genes known to be mutated in MDS and other leukemias, and they identified mutations in these genes in samples from 738 patients with MDS. They found recurrent mutations in 43 of these genes. For the 24 genes most frequently mutated, mutations in one (SF3B1) were associated with a favorable outcome (consistent with several recent publications), and mutations in eight other genes were associated with worse outcome, compared to patients that lacked these mutations. This team went on to show that mutations in this set of genes could predict survival as effectively as existing prognostic tools that utilize blood count values and bone marrow chromosome analysis. It is worth pointing out that tests for these mutations are not currently available to patients (outside of research centers), but if these results are confirmed, it should motivate companies to develop these tests and could lead to changes in the way we diagnose and risk-stratify MDS patients in the near future. In addition to known genes, several groups reported discoveries of several new genes that are recurrently mutated in MDS. One example is an abstract that was presented at the Plenary Session on the second day of the meeting (Makishima, et al). This team, from the Cleveland Clinic and collaborating sites, identifi ed mutations in a gene called SETBP1 in patients with MDS and other myeloid leukemias. Although the frequency of mutations in SETBP1 is low in MDS, the investigators noted that inherited mutations in this gene are known to cause a rare syndrome that includes predisposition to a variety of cancers. This adds to a growing list of genes that can contribute to cancer when mutations are inherited (in these rare familial syndromes), but also contribute to cancer when mutations in these same genes are acquired later in life (in “sporadic” cancers, without a family history).

In drug development, or new protocols for existing drugs, were there any research trends that seemed particularly promising or intriguing?

One area here that I would comment on pertains to the intersection between genetics and response to existing drugs (alluded to above). In other words, researchers are asking whether mutations detected in MDS samples can predict how well patients will respond to existing drugs. One of the themes in MDS genetics that has emerged over the past several years is that several drugs we currently use target the pathways that are also frequently mutated in patients with MDS. This raises the question of whether patients that have mutations in these genes/pathways might be more (or less) sensitive to these therapies. The relevant therapies here include drugs that impact DNA methylation (e.g., azacytidine, decitabine) and drugs that impact histone acetylation (e.g., vorinostat, panobinostat). Results from at least four large studies addressing these questions were presented at the ASH meeting. My overall impression so far is that we have not identifi ed a “smoking gun”; in other words, mutations in a gene or genes that reliably predict patients who will achieve a good response to these therapies. This may be because the hypothesis is not correct, meaning that mutations in these genes are not predictive of response. Or, it may be that we are not looking at the best combination of genes, or the number of patients included in these studies is too small, or some combination of these factors and others. This continues to be an active area of research, so I would encourage everyone to “stay tuned” for more results.

Was there any one paper, presentation, or particular subject that seemed the most signifi cant with regard to the overall direction of MDS research?

One area of MDS research that deserves comment is the importance of experimental models that can be used in the laboratory. These include cell lines derived from MDS patients or genetically altered strains of mice that accurately model human MDS. We have very few of these, and this limits progress in understanding how the disease works and how we can develop better therapies. Several groups are trying a new strategy to develop model systems that involve something called “induced pluripotent stem cells” or iPSCs. These are cells created in the laboratory that can be grown indefi nitely and retain the genetic abnormalities present in the starting cells. These cells are “pluripotent”, which means that they can be coaxed from their undiff erentiated “stem cell-like” state into diff erentiated cells, including blood cells. A key characteristic of these cells is that they can be created from adult cells (e.g., bone marrow cells). An ASH abstract from a group led by Eirini Papapetrou at the University of Washington in Seattle (Boussaad, et al) described the generation of iPSCs from the bone marrow of four patients with MDS. This work is extremely promising and if extended and replicated by other groups, could provide a strategy for creating panels of iPSCs from MDS patients. These cells could be extremely useful for furthering our understanding of the biology of MDS and for devising new therapeutic approaches.

What do you think MDS patients would most want to know about the state of research as it was presented and discussed at ASH 2012?

I think it is important to point out that the quality and number of presentations on MDS were higher at this meeting than any ASH meeting I have attended over the past 20 years. Patients should fi nd it encouraging that there is so much good work going on in this fi eld. Although it will take time for these new discoveries to be translated into improvements in diagnosis and treatment for MDS, there is good reason to be optimistic that outcomes for our patients will improve in the coming years.

Timothy Graubert, MD

Lead Photo
Position / Title: 
Director, Hematologic Malignancies Program, Hagler Family Chair in Oncology, Professor of Medicine
Massachusetts General Hospital, Harvard Medical School

Dr. Graubert’s research focuses on the molecular pathogenesis of myeloid leukemias. While at Washington University in St. Louis, he and his colleagues used genome sequencing technology extensively to gain insights into the genetic basis of human cancer and to use this information to improve risk stratification tools and identify targets for novel therapy.  Their group published the first complete genome sequence of a human cancer (acute myeloid leukemia) in 2008 and in subsequent publications described novel recurrent mutations in IDH2 and DNMT3A that have prognostic significance in acute myeloid leukemia.  Dr. Graubert’s research group identified novel mutations in U2AF1 in patients with myelodysplastic syndrome, helping to open a new line of investigation into the role of splicing gene mutations in the pathogenesis and treatment of myeloid leukemias.  Dr. Graubert also led the group that performed the first whole genome sequencing studies in myelodysplastic syndrome that led to new understanding of how this disease is initiated and then evolves when patients progress to acute leukemia.  In 2013, Dr. Graubert moved to Massachusetts General Hospital where he directs the Hematologic Malignancy Program.  Currently, research in the Graubert laboratory is focused on two main projects: 1) understanding the mechanism of spliceosome-mutant MDS/AML, and 2) the molecular genetics of familial MDS/AML.