Grant Recipients

For nearly 30 years, AAMDSIF has provided research grants totaling in excess of $5 million to an international group of more than 90 researchers to help advance the understanding and treatment of aplastic anemia, myelodysplastic syndromes (MDS), and paroxysmal nocturnal hemoglobinuria (PNH).

The two-year grants have helped bring forth new insights into the causes and therapeutic approaches for these diseases. These grantee profiles present the grantees by year the awards were granted, and a summary of their grant-funded research projects.

Research Fund

Grant Year: 2018

Sydney Lu, MD, PhD

Harold Spielberg Research Fund

Recurrent change-of-function mutations in RNA splicing factors are frequent in patients with myelodysplastic syndromes (MDS) and related myeloid neoplasms. Splicing factor mutations most typically occur as heterozygous mutations at recurrent ‘hotspots’ along the amino acid sequence and in a mutually exclusive manner with one another. Although much remains to be learned about how these mutations promote MDS development, recent results from our lab and others have demonstrated that cells expressing these mutations are preferentially sensitive to further alterations to the RNA splicing process. Exploiting the selective vulnerability of splicing factor mutated myeloid neoplasms to further splicing inhibition has led to clinical development of drugs targeting...

Isabel Mérida, PhD

Mary Pat Madden

Aplastic anemia is a disease in which the bone marrow gradually stops producing red and white blood cells and platelets. As a result, people with aplastic anemia feel tired, may bleed more easily and are at higher risk of having infections. Aplastic anemia can strike at any age but is more often diagnosed in children, young adults and older people. In a few cases aplastic anemia is passed from parents to their child, but most often this disease results from destruction of the cells in the bone marrow by overactive immune system blood cells called T-cells. Healthy T cells are "trained" to recognize and destroy exclusively foreign invaders of the body, such as viruses. But in some cases, T cells attack the cells from the body, causing autoimmune diseases like lupus or rheumatoid arthritis...

Grant Year: 2017

Coleman Lindsley, MD, PhD

Harold Spielberg Research Fund

Myelodysplastic syndrome (MDS) is a diverse group of bone marrow diseases, unified by poor blood counts and a propensity for development of acute leukemia. MDS is most often diagnosed in older adults, arising as part of aging and without a toxic exposure or predisposing medical condition. In rare cases, however, MDS develops as a complication of an inherited bone marrow disease, such as dyskeratosis congenita, which causes a defect in telomere maintenance and have an increased risk of developing MDS and leukemia. Telomeres are caps that protects the ends of chromosomes from deterioration, and are important for preventing premature cellular aging. In preliminary studies in a large international cohort of MDS patients, we found that an unexpectedly high number of MDS patients have inherited...

Joseph Oved, MD

James D. Moreland Research Fund, Mary Pat Madden

Aplastic Anemia is a disease that results in the destruction of hematopoietic stem cells in the bone marrow by the immune system. Although the exact mechanism of this pathology is not fully understood, the prevailing model proposes that the immune system and specifically T cells are responsible for this destruction. Pediatric and adult aplastic anemia, while clinically similar in their presentation may in fact be representative of different subsets of a spectrum of aplastic anemia. Our group and others have shown that adult patients with aplastic anemia have a tendency to develop cell populations that are predisposed to myelodysplastic syndrome and leukemia. In the pediatric population however, we found that patients tend to develop cell populations that have mutations in certain genes (i...

Sergei Vatolin, PhD

Patricia and Vincent Geczik Legacy Fund

Medicines available to the patients with severe blood diseases like aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are very limited. The idea of improvement the quality of blood cells with small molecules may give a new opportunity to cure AA and hope to reverse PNH. Our proposal is based on discovery of drugs (TCC1 and TCC2) which improve performance of blood stem cells by increasing their life span. We hypothesize that the unique biological activity of these agents can already be used in clinic to treat AA and PNH by restoration the function of damaged/exhausted blood stem cells. Such effects may help to alleviate diseases and accelerate recovery of normal blood in patients with AA or PNH. The objective of this study is preclinical testing of the identified drugs to...

Grant Year: 2016

Akihide Yoshimi, MD, PhD

Shirley and James O’Brian Research Fund

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by inefficient blood production. MDS represents the most common cause of acquired bone marrow failure in adults and there are few effective therapies for the majority of MDS patients. In 2011, it was discovered that mutations in proteins encoding RNA splicing factors (SFs) are the most common class of mutations in patients with MDS and chronic myelomonocytic leukemia (CMML). Despite these discoveries, however, we do not yet fully understand why abnormal RNA splicing results in MDS nor do we have therapies that specifically target MDS cells bearing this common class of mutations. The goals of this proposal are two-fold: (1) to determine the efficacy of clinical-grade novel spliceosome inhibitors in...

Tushar Bhagat, PhD

Carol and Peter Stewart Fund in memory of Raymond Hodor

Myelodysplastic syndromes (MDS) are a heterogeneous set of clonal disorders characterized by ineffective blood cell development. These diseases are driven by many complex genetic and non-genetic changes. Recent findings have uncovered that alterations in the bone marrow microenvironment contribute to the disease. In our preliminary data, we have found that the beta-catenin pathway is activated in the bone marrow and in the blood of patients with MDS and this predicts a poor clinical outcome. We demonstrate that changes in the stroma increase beta-catenin in the MDS cells and can be targeted by new drugs. We will utilize mouse models, cells lines and patient samples to understand how the bone marrow environment is altered in patients and utilize newly developed beta-catenin pathway...

Alina Dulau Florea, MD

Patricia and Vincent Geczik Legacy Fund

Summary Our study involves the analysis of normal and abnormal cells in the bone marrow of patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). In this condition, due to a gene mutation, some bone marrow cells and their progeny in the blood lack an important cell surface component that functions as an anchor for other proteins, some of which attach to blood cells and protect them from destruction by complement, part our immune system. The result of this deficiency is a breakdown of red cells. If large quantities of red cells are destroyed, people become very tired, or have pain in the belly, head or when swallowing, or develop blood clots. The cause of the gene mutation is unknown. Some patients with other conditions, such as aplastic anemia (AA, a disease where marrow stops...

Kate MacNamara, PhD

Julia Malsin Research Fund

Bone marrow failure is the rare but devastating collapse of blood production, and if left untreated the disease is invariably fatal. Our current therapies are inadequate in the sense that they involve general immunosuppression or highly invasive treatments via bone marrow transplantation. In both genetic and acquired cases of bone marrow failure, excessive inflammation ultimately causes destruction of the stem cells required to maintain daily production of all blood cells. Inflammatory molecules such as interferon gamma (IFN-gamma) are known to contribute to pathology, yet exactly how stem cell function is compromised by these factors is not clear and remains an important question in understanding the pathogenesis of bone marrow failure. We utilized a mouse model of bone marrow failure...

Grant Year: 2015

Jing Fang, MD, PhD

Michael Fernandes Research Fund

A major complication of myelodysplastic syndromes (MDS) is worsening cytopenias due to bone marrow failure. Novel therapeutic approaches are urgently needed for MDS, as current therapies have modest responses and many patients are not suitable candidates for bone marrow transplantation. Our preliminary study revealed a role of sequestosome 1/p62 in the pathogenesis and disease evolution of MDS. For this study, we will dissect the functional domains on p62 and associated signaling pathways that are necessary for the development and maintenance of MDS. Moreover, we propose to target p62-intacting complexes using a peptide approach as an attempt to target MDS clones and prevent disease evolution. This study will improve our understanding of MDS-associated bone marrow failure and may reveal...