Abstract
The PLCG1 gene, which encodes the phospholipase C γ1 isoform, is located within the commonly deleted region of the long arm of chromosome 20 (del(20q)) observed in myelodysplastic syndromes (MDS). Phospholipase C is involved in diverse physiological and pathological cellular processes through inositide signaling. We hypothesized that reduced PLCG1 expression because of haploinsufficiency by del(20q) plays a role in the molecular pathogenesis of MDS. Therefore, we analyzed PLCG1 expression in bone marrow mononuclear cells at diagnosis in 116 MDS patients with or without del(20q) by quantitative RT‐PCR to evaluate its clinical significance. The expression level of PLCG1 was significantly lower not only in MDS patients with del(20q) but also in those without del(20q) compared to that of the controls, which suggests that reduced PLCG1 expression is a common molecular event in MDS. Patients in the lowest quartile (Q4) group for PLCG1 expression had lower overall survival (OS) compared to that of other patients (Q1‐Q3) (log‐rank test, P = .0004) with estimated median OS times of 22 in the Q4 group and 106 months in the Q1‐3 group. Univariate and multivariate analysis indicated reduced PLCG1 expression (Q4) was associated with lower OS (hazard ratio 2.58, 95% CI 1.35‐4.84, P = .0049), which suggests that reduced PLCG1 expression is an independent prognostic factor for OS. In addition, patients were well‐stratified for OS by combining PLCG1 expression level (Q4 vs Q1‐3) and bone marrow blast percentage (5% or more vs less than 5%). Thus, the level of PLCG1 expression at time of diagnosis is a prognostic biomarker for MDS.
Highlights
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and an increased risk of leukemic transformation
A significant reduction in PLCG1 expression was observed in MDS patients compared to that of control subjects
We found that the PLCG1 gene is located within the common deleted region (CDR) of del(20q) observed in MDS.[6]
Summary
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and an increased risk of leukemic transformation. In approximately half of MDS cases, chromosome abnormalities are found, and monosomy and chromosome deletions are frequently observed These deleted chromosomal regions contain tumor suppressor genes that are involved in the development and progression of MDS. Decreased expression of these candidate tumor suppressor genes by haploinsufficiency because of chromosome loss may play a role in MDS molecular pathogenesis. Deletion of the long arm of chromosome 20, del(20q), is observed in approximately 5%-10% of MDS cases.[1,2] Several research groups, including ours, have examined the common deleted region (CDR) of del(20q) by different molecular biological approaches.[3,4,5,6,7] We hypothesized that genes located within the CDR are involved in the pathogenesis of MDS because of haploinsufficiency. We analyzed PLCG1 expression in bone marrow mononuclear cells at diagnosis in MDS patients with or without del(20q) and investigated its clinical significance
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