Papaemmanuil, Elli, Ph.D.

Elli Papaemmanuil, Ph.D.
Biological Consequences of SF3B1 mutations in MDS

Elli Papaemmanuil, Ph.D.

Memorial Sloan-Kettering Cancer Center

2016 Grant Recipient

Biological Consequences of SF3B1 mutations in MDS

EvansMDS Discovery Research Grant 2016


Myelodysplasia (MDS) is a prevalent blood cancer that affects the cells in the bone marrow that normally sustain blood formation, called hematopoietic stem cells (HSCs). Similar to most cancers, MDS arises when cells mutate propagate and mutate again. These mutations impair normal blood cell development and result in the accumulation of large cell populations in the bone marrow that do not function properly, resulting in anemia, frequent infections and often disease progression to severe and lethal blood cancers.

In recent years breakthroughs in technologies for DNA sequencing made the analysis of genomes from a large number of MDS patients possible. These analyses reveal that almost all patients harbor at least one mutation in their blood cells and the majority of them have two or more. Strikingly these mutations affect specific biological networks and the presence of these mutations and their combinations are major determinants of the clinical presentation and the course of the disease. For example certain mutations associate with mild cytopenia and favorable outcomes, manifested by long-term survival of patients whereas others manifest with aggressive disease and short survival. These new insights give us exciting opportunities to better understand how the disease develops by investigating the effects that these mutations exert on the blood cells, particularly the HSCs. Understanding the biology of MDS is crucial to improve clinical management of MDS patients and importantly develop new and effective therapies.

However, our ability to study these mutations and understand how these cause MDS is met with significant challenges. There are more than 80 genes that are recurrently mutated in MDS and most patients have multiple mutations. Thus the number of genetic combinations is very high. Consequently studies of how gene mutations affect disease biology require large numbers of samples or selection of uniform genetic characteristics – for example patients with the same 2 or 3 mutations. Additionally, studies of the cells affected by these mutations, the HSCs can also be challenging. HSCs are very rare cells and their isolation from patient bone marrow yields very low numbers that are not sufficient to study with most current methods. Therefore most studies use bulk samples from the bone marrow, which contain a vast diversity of cell types. This diversity often produces unclear or hard to interpret results. Last, a common approach to study the effects of mutations in cancer is to introduce the same mutations in model organisms such as the mouse. Whilst these provide important insights, the relevance of any conclusions is limited because of important species differences in physiology and disease between human and mouse.

This proposal unites inter-disciplinary expertise in MDS to address some of these challenges. Dr. Papaemmanuil is a leading computational biologist in MDS research. Dr. Papaemmanuil’s research has led to the discovery of key gene mutations that cause MDS. More recently Dr. Papaemmanuil has used profiling of large (>1000) number of MDS patients to understand the important combinations of gene mutations that lead to MDS and how these affect clinical presentation, response to therapy and disease progression. The present proposal is informed by these studies, selecting to study patients with uniform genetic profiles. Additionally to overcome some of the challenges in MDS research, Dr. Papaemmanuil and Dr. Papapetrou have developed innovative technologies in their laboratories. Dr. Papaemmanuil has developed methods to analyze very small cell numbers (as low as one single cell). To address the limitation in studying primary cells isolated directly from the patients Dr. Papapetrou has developed a method to convert patient cells into induced pluripotent stem cells (iPSCs). iPSCs can be expanded to very large numbers permitting for the first time extensive experimentation into the biology and downstream consequences of the key mutations in MDS. Dr.a Papapetrou has also developed a series of assays to study how normal blood production is impaired in patients with MDS thus enabling research that links the genetic causes to the mechanisms of MDS. By combining the expertise of both laboratories in diverse and complementary research areas, we plan to tackle the pathogenesis of MDS by focusing on the most frequent subset of MDS patients with mutations in the SF3B1 gene. This is because population genetics and clinical association studies have provided evidence that this MDS subset holds an important key to the pathogenesis of MDS. We expect that the proposed studies will allow us to analyze the effects of SF3B1 mutations in unprecedented detail and depth for the first time and open new avenues for the treatment of MDS.