HMGA2 Dysregulation in Myelofibrosis with Myeloïd Metaplasia (MMM) Versus Other Phi-Negative Chronic Myeloproliferative Disorders and Myelodysplasia.

Abstract Background: Dysregulation and overexpression of the tumorigenic gene HMGA2 has been demonstrated in the mononuclear cells of 12 consecutive MMM patients (pts) and thus appears a hallmark of the disease [Andrieux & al. Genes, Chromosomes and Cancer 2004]. Apart from pathogenetic considerations, the consistency of this finding raises the question of its specificity and usefulness as a differential diagnosis tool able to distinguish proliferative forms of MMM from other chronic Phi negative myeloproliferative diseases and on the other hand cytopenic forms of MMM from myelodysplasia. Material and methods: We assessed the level of HMGA2 expression in 30 MMM pts (the former series and 18 additional pts), 15 healthy volunteers as controls, 20 pts with Polycythemia vera (PV), 5 having evolved to post-polycythemic myelofibrosis (PPMF), 12 pts with Essential Thrombocytemia (ET), 3 of whom having developed fibrosis (PTEMF), 1 pt with a MMM-like picture due to systemic mastocytosis and 15 patients presenting with various types of MDS, 3 of whom having marked medullary fibrosis. RNA was extracted from peripheral blood leukocytes separated by standard Ficoll centrifugation and QT-PCR was performed on cDNA with TaqMan technology. Results: While controls were all negative, a substantial expression of HMGA2 was confirmed in 28/30 MMM pts, significantly higher than in any other situation; PV and ET patients were negative except for those having developed myelofibrosis; the pt with myelofibrosis related to mastocytosis was also negative. In the short and heterogeneous series of MDS pts, a weak expression was occasionnaly found with no obvious correlation with myelofibrosis or the subtype of MDS. Conclusions: dysregulation and overexpression on HMGA2 characterize MMM and allow a definite discrimination from other Phi-negative MPD; in PV or ET, the gene is not expressed during the chronic proliferative phase but becomes activated in the case of an evolution towards myelofibrosis. These findings, together with the presence of transcripts in MDS, suggest that the re-activation of HMGA2 is not directly linked to the myeloproliferation nor to the myelofibrosis itself but rather associated with dysplastic hematopoïeisis either primitive or subsequent to myelofibrosis.