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 splicing factor-mutant versus wildtype MDS and CMML models and (2) to determine the mechanistic basis for the therapeutic efficacy of spliceosomal inhibitory compounds in more detail. We hypothesize that the presence of any of the commonly occurring SF mutations found in myeloid malignancies will sensitize cells bearing these mutations to further perturbation of spliceosome function. To accomplish our goals and test these hypotheses, we propose to use novel patient-derived xenograft (PDX) models of MDS and CMML as well as isogenic cells with and without SF mutations. We will then use these models to understand the specific mechanisms for the therapeutic efficacy of a novel spliceosome inhibitor with immediate clinical potential.
The innovative aspects of this proposal include the use of novel PDX model of MDS and CMML. Our preliminary data highlight the applicability of this xenograft model to MDS and CMML. We expect our research to further our understanding of how MDS develops, and ultimately to lead to the identification of new drugs and therapeutic approaches for treating MDS. If successful, this proposal could have tremendous therapeutic impact for patients with bone marrow failure due to MDS.
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. There are few effective therapies for the majority of MDS patients. An important reason that relatively few therapies are available is that we have an incomplete understanding of why and how MDS develops. In 2011, researchers discovered that most patient with MDS carry genetic mutations that spontaneously developed in the bone marrow, ultimately affecting a molecular process called RNA splicing. RNA splicing is the process wherein genetic information is read from DNA and then used to make proteins. However, despite these research breakthroughs in determining the set of spontaneous genetic mutations that are associated with MDS, we do not yet fully understand why abnormal RNA splicing results in MDS. Moreover, we do not yet have therapies that specifically target MDS cells bearing this common class of mutations. Thus, the goals of this proposal are two-fold: (1) to determine how spliceosomal gene mutations result in development of MDS in more detail and (2) to develop new therapies specifically aimed at eradicating MDS cells that carry spliceosomal gene mutations.
To accomplish our goals and test these hypotheses, we propose to use combination of novel animal models and a clinical-grade drug. In the first year of the grant, (1) we characterized our novel animal models using patient-derived leukemia cells to fully utilize them for preclinical evaluation of therapeutic compound and we have published these results in Blood (Yoshimi et al. “Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML” Blood 2017), (2) we took advantage of these novel animal models to test the efficacy of a clinical-grade novel spliceosome inhibitor and showed that the presence of splicing factor mutations sensitize cells to the drug.