Dysregulation of BMPR2, Arginase II and HMGA2 Expression in Idiopathic Myelofibrosis and Secondary Myelofibrosis.

Idiopathic myelofibrosis (IMF) is a fatal clonal myeloproliferative disorder, characterized by variable pancytopenia, splenomegaly, leukoerythroblastic blood smear, marrow fibrosis (MF), and myeloid metaplasia. Like all myeloproliferative disorders, it is due to an acquired somatic mutation of a single hematopoietic progenitor. MF has also been reported in systemic lupus and metastatic malignancies involving bone marrow. We have recently demonstrated the occurrence of MF in 85% patients with pulmonary hypertension (PH), which (unlike IMF) is associated with polyclonal hematopoiesis and normal number of circulating CD34+ cells. The pathophysiological mechanisms resulting in IMF and secondary MF (SMF) in PH remain still unclear. To date, 52 heterozygous germline mutations in the gene ( BMPR2 ) encoding the bone morphogenetic protein type II receptor (BMPR-II) have been found to characterize many cases of familial (Lane, 2000) and sporadic primary PH (PPH) (Thomson, 2000). Recently, increased activity of arginase in pulmonary tissue of patients with PH was found. This may contribute to the pathogenesis of pulmonary hypertension by decreasing the substrate for NO synthesis. We examined BMPR2 and Arginase II mRNA levels by quantitative real-time RT-PCR in mononuclear cells (MNC), platelets (PLT) and granulocytes (GNC) from IMF patients and PH patients with secondary MF. We show for the first time that the mRNA level of BMPR2 is increased in PLT and GNC of IMF compared with normal controls. Arginase II mRNA was significantly increased in GNC of IMF as well as PH patients with SMF. Rearrangement and over expression of high-mobility group AT-hook2 ( HMGA2 ) gene in myeloid progenitors in two patients with IMF was recently reported. This gene is known to play a major role in fetal growth and development, and is expressed in trace amount in adult lung, kidney, and synovia. We found significantly increased HMGA2 mRNA expression in MNC of IMF patients. In summary, the biomarkers studied here can be abnormal in both IMF and PH with secondary MF and may not be useful to discriminate between the two types of MF. Dysregulation of BMPR2 , Arginase II and HMGA2 expression may play a pathophysiological role in MF of both IMF and PH. Expression of BMPR2 , Arginase II and HMGA2 in Blood Cells of IMF and SMF | Gene | Cells | Control ( Δ CT) | Idiopathic MF ( Δ CT) | Secondary MF ( Δ CT) | |:----------------------------------------------------------------------------------------------------------------------------------------------------------------:| ----- | --------------- | --------------------- | -------------------- | | *The P value represents a significant difference of gene expression in IMF or SMF compared with normal controls. A lower ΔCT indicates a higher gene expression. | | BMPR2 | PLT | 18.5±1.2 | 16.7±1.4 (p=0.038) * | 18.4±2.2 (p=0.881) | | | GNC | 19.2±1.0 | 18.3±1.3 (p=0.009) * | 19.1±1.2 (p=0.893) | | | MNC | 18.3±1.2 | 19.2±1.8 (p=0.059) | 19.0±2.7 (p=0.554) | | Arginase II | GNC | 24.5±0.6 | 21.9±1.7 (p=0.000) * | 22.6±1.2 (p=0.004) * | | | MNC | 24.4±3.5 | 24.4±3.9 (p=0.965) | 22.5±2.4 (p=0.222) | | HMGA2 | MNC | 32.4±1.6 | 29.3±1.7 (p=0.000) * | 30.8±1.8 (p=0.085) |