Over the past decades, an emerging role of phosphatases in the pathogenesis of hematologic malignancies and solid tumors has been established. The tumor-suppressor protein phosphatase 2A (PP2A) belongs to the serine-threonine phosphatases family and accounts for the majority of serine-threonine phosphatase activity in eukaryotic cells. Numerous studies have shown that inhibition of PP2A expression and/or function may contribute to leukemogenesis in several hematological malignancies. Likewise, overexpression or aberrant expression of physiologic PP2A inhibitory molecules (e.g., SET and its associated SETBP1 and CIP2A) may turn off PP2A function and participate to leukemic progression. The discovery of PP2A as tumor suppressor has prompted the evaluation of the safety and the efficacy of new compounds, which can restore PP2A activity in leukemic cells. Although further studies are needed to better understand how PP2A acts in the intricate phosphatases/kinases cancer network, the results reviewed herein strongly support the development on new PP2A-activating drugs and the immediate introduction of those available into clinical protocols for leukemia patients refractory or resistant to current available therapies.
Abstract: Using quantitative fluorescence in situ hybridisation and flow cytometry (flow‐FISH), we investigated the biological and clinical relevance of telomere length in 55 patients affected by myelodysplastic syndromes (MDS) compared with 55 sex‐ and age‐matched controls. We found that telomere fluorescence in MDS granulocytes, and CD34+ cells did not decline with age as in normal controls and that MDS granulocytes and CD34+ cells had significantly shorter telomeres than healthy controls. A significant higher incidence of cases with intermediate‐unfavourable cytogenetics and International Prognostic Scoring System (IPSS) int‐2/high‐risk group was observed among patients with lower telomere fluorescence. We also found that apoptosis in CD34+ cells was significantly higher in IPSS int‐1 low‐risk patients when compared with IPSS int‐2 high‐risk cases and healthy controls and that CD34+ cell telomere fluorescence directly correlated with CD34+ cell apoptosis. Reduced telomere fluorescence was associated with a history of occupational exposure to toxic agents and with worse survival in univariate and multivariate analyses. Our results suggest that flow‐cytometry assessment of telomere dynamics may represent a valuable tool in the biological and clinical–prognostic characterisation of MDS disorders.
Thrombosis of the cerebral veins or sinuses is a rare cerebrovascular disorder, which seldom represents a complication of acute promyelocytic leukemia. To the best of our knowledge, it never occurred during treatment with all-trans retinoic acid. We report a case of a 35-year-old woman affected by acute promyelocytic leukemia, who developed massive thrombosis of the cerebral sinuses and veins when she was in complete morphological and molecular remission after all-trans retinoic acid and idarubicin treatment. Anticoagulant therapy contributed to progressive dissolution of the thrombosis as documented by magnetic resonance imaging with complete disappearance of neurological signs without sequelae.
The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNA CCAT2 in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. We further identified that CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by down-regulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel non-APOBEC, non-ADAR, RNA editing at the SNP locus in MDS/MPN patients and CCAT2 -transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies.
