Altered Expression and Mutation Analysis Of Heterogeneous Nuclear Ribonucleoprotein k In Bone Marrow Of Primary Myelofibrosis Patients

The heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA/DNA-binding proteins that consist of several family members: A1, A2, B1, C2 and K. hnRNPs have been implicated in numerous cellular processes and when dysregulated, have been suggested to impact tumorigenesis. hnRNP A2/B1 is overexpressed in some lung cancers and has been suggested to be a useful early detection marker for lung carcinoma. hnRNP K has been reported to associate with colon cancer and directly interacts with DNA, RNA, and proteins to regulate gene expression in numerous cellular processes involved in mitogenic responses and tumorigenesis. Loss of hnRNP K expression results in defects in differentiation and apoptosis, and increased hnRNP K expression has been associated with loss of apoptosis and an increase in cellular proliferation.

To explore the possibility of altered hnRNP K expression or mutations in primary myelofibrosis, we isolated mRNA from primary blood or bone marrow mononuclear cells from patients with myelofibrosis (n=62) and healthy controls (n=19). We examined hnRNP K levels and determined that hnRNP K is significantly overexpressed in myelofibrosis (p= <0.0001). Sequencing of the hnRNP K locus revealed a single nucleotide alteration (A-to-G) one allele of intron 5 in 43% of myelofibrosis patients (n= 21) In contrast, only one out of 11 control samples harbored this alteration ((x² p = 0.05). At present, we are investigating whether G allele is a mutation or a SNP. Furthermore, western blotting indicates an increase in phosphorylation of serine-248 in myelofibrosis patients. Together, these data suggest altered hnRNP K expression and mutations in myelofibrosis that might play a significant role in myeloproliferation and hematopoietic differentiation in myelofibrosis patients. Given the significant impact that hematopoietic differentiation has on leukemogenesis, it is imperative to decipher