GR SNP helps transform myelofibrosis

In this issue of Blood, Poletto and colleagues examine the association of A3669G single nucleotide polymorphism (SNP) of human glucocorticoid receptor (GR) in patients with primary myelofibrosis (PMF), demonstrating a significantly higher frequency of this allele in these patients than in 2 cohorts of healthy individuals.¹ 

The GR A3669G SNP was also associated with a higher white blood cell count, higher spleen index, and a higher frequency of peripheral blood (PB) CD34-positive cells in PMF. Furthermore, among the patients with JAK2V617F-mutated PMF, the transformation-free and overall survival were significantly shorter in patients homozygous for the GR A3669G.

Cancer susceptibility genes as well as genes that predict a higher risk of transformation from an indolent to a more aggressive state of the disease are of particular interest as these can identify patients at risk and may allow modifications in management that alleviate or delay disease-associated complications. Among hematologic malignancies, transformation from a less aggressive to a more acute status is commonly associated with a poor prognosis, giving rise to entities that are more sinister than their de novo counterparts. Transformation to a disease that phenotypically is considered to be acute myeloid leukemia (AML) is seen in patients with myeloproliferative neoplasms (MPNs) as well as myelodysplastic syndromes, and is termed “blast phase” in the former.²  Such a variant of AML is commonly insensitive to traditional cytotoxic chemotherapy, is frequently associated with a rapid decline, and can only be cured in the minority of cases using an allogeneic stem cell transplant. Therefore, identification of predictors of disease transformation as well as development of more effective therapeutic strategies in this setting is of particular importance.³ 

Several recent reports have examined the clinical predictors as well as potential molecular events that predispose to the transformation to AML in patients with PMF. In a study of 311 patients from the Mayo Clinic, percentages of PB blasts ≥ 3% and/or platelet count < 100 × 10⁹/L were the only independent predictors of leukemic transformation.⁴  In another study from the same institution, presence of unfavorable karyotype [including complex, +8, −7/7q−, −5/5q−, i(17q), inv(3), 12p−, or 11q23] and low platelet count but not the International Prognostic Scoring System (IPSS) score were independent predictors of leukemia-free survival with 5-year leukemia transformation rates of 46% versus 7% for patients with unfavorable and favorable karyotypes, respectively (hazard ratio: 5.5, P < .0001).⁵  Other investigators, using high-resolution single nucleotide polymorphism (SNP) arrays, have compared chromosomal abnormalities in samples from patients with MPN to those with transformed disease (MPN-BP) and identified an increased number of genomic alterations in the transformed specimens including aberrations of ETV6 and TP53 as well as new candidate genes on 7q, 16q, 19p, and 21q.⁶ 

Similarly, mutations in several genes including IDH1 and IDH2, TET2, RUNX1, and TP53 and SRSF2 have been reported to be involved in the transforming events that contribute to the leukemic transformation in patients with MPNs including PMF.^7-11 

With increasing understanding of the molecular biology of such disease transformation, we are likely to better comprehend the process and potentially identify strategies to prevent or reverse it. The identification of the GR A3669G SNP as a predisposition factor for PMF and its potential collaboration with other molecular events to lead to leukemic transformation is another welcome discovery in study of this lethal disease.