Investigation of the Significance of Son Isoform mRNA Expression in Patients with Blood Cytopenias with/without Evidence of Myeloid Neoplasia

Myelodysplastic Syndrome (MDS) refers to hematopoietic neoplasms characterized by defective development of myeloid progenitors (erythrocytic, granulocytic, and megakaryocytic cell lines) and bone marrow. Clinical signs are characterized by blood cytopenias that can affect one or all three myeloid cell lines and bone marrow irregularities. Because of this heterogeneity, patients can present with anemia, thrombocytopenia, and/or neutropenia and it is important to determine prognosis, severity, and progression. Currently, the standard method for determining a diagnosis of MDS is based on metaphase cytogenetics which is limited in its scope. Other newer karyotyping procedures such a fluorescent in situ hybridization and single nucleotide polymorphism assay have improved the ability to evaluate patients. However, these tests still do not establish conclusive key fundamental biomolecular-genetic origins. It is hoped that in the future diagnostics will include information that further supports development of clinical prognostic and therapeutic options.

Many mutational abnormalities have been discovered in MDS. The mutation of interest in this investigation is a shortened isoform of the SON protein which has been implicated to contribute to the pathogenesis of MDS, acute myelogenous leukemia (AML), and other malignancies. SON is a splicing cofactor that regulates the cell cycle and stability by interacting with genes and proteins known to contribute to tumorigenesis. Samples were obtained from patients being evaluated for cytopenia, MDS, AML, and other myeloid neoplasms and compared SON mRNA expression levels to control samples. Prior studies found that alternative splicing of the SON gene produces SON B and SON E both of which are truncated and aberrantly upregulated in patients with hematopoietic malignancies. The short SON isoforms antagonize the normal functions of full-length SON (SON F) leading to repression and splicing dysregulation of key cell cycle genes such as mixed lineage leukemia (MLL) family methyltransferases. SON regulates MLL complex-mediated histone methylation; this process requires the binding of menin, a tumor suppressor. The truncated SON isoform prevents this binding of meninto the MLL complex while opposing the transcription repressing function of full-length SON. A collaborative study between the laboratory of Dr. E.Y. Ahn and the hematology clinic of the Mitchell Cancer Institute further investigates the relationship between SON expression and hematopoietic disorders. SON E was found to be upregulated patients with anemias, MDS, and other myeloid neoplasms, a finding consistent with preceding research. Iron replete subjects and subjects taking erythropoietin did not follow his pattern. This new insight has yet to be explored due to limited data.

In this study, samples were obtained from consented participants with cytopenias, MDS, or myeloproliferative disorders and analyzed for SON mRNA expression. Investigation revealed SON expression is abnormal in the majority of patients tested with cytopenias from either iron deficiency or myeloproliferative neoplasms or myelodysplastic syndrome. The differential expression of SON E appears to increase in patients with myeloproliferative neoplasms, myelodysplastic syndrome but differ in expression among patients. Deviations from the expected SON E short isoform expression were discovered for iron replete patients and a patient taking erythropoietin, leading to the conclusion that further clinical correlation of the SON expression in patients with iron deficiency and no MPD or MDS may further elucidate SON expression relevance in this disease and the relation to iron metabolism. In the future, longitudinal inspection of laboratory values and SON expression in patients with and without treatment is expected with specific emphasis on total body iron status as well as comparison to other mutational data (RUNX1 and GATA1). Overall, the results displayed potentiate SON isoform expression may be important in understanding the pathogenesis of malignant and non-malignant diseases of the blood.