ERG Deregulation Induces PIM1 Over-Expression and Aneuploidy in Prostate Epithelial Cells

The ERG gene belongs to the ETS family of transcription factors and has been found to be involved in atypical chromosomal rearrangements in several cancers. To gain insight into the oncogenic activity of ERG, we compared the gene expression profile of NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG. We found that all three ERG fusions significantly up-regulate PIM1 expression in the NIH-3T3 cell line. PIM1 is a serine/threonine kinase frequently over-expressed in cancers of haematological and epithelial origin. We show here that tERG expression induces PIM1 in the non-malignant prostate cell line RWPE-1, strengthening the relation between tERG and PIM1 up-regulation in the initial stages of prostate carcinogenesis. Silencing of tERG reversed PIM1 induction. A significant association between ERG and PIM1 expression in clinical prostate carcinoma specimens was found, suggesting that such a mechanism may be relevant in vivo. Chromatin Immunoprecipitation experiments showed that tERG directly binds to PIM1 promoter in the RWPE-1 prostate cell line, suggesting that tERG could be a direct regulator of PIM1 expression. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability

Decitabine treatment for an unusual case of atypical chronic myeloid leukemia (aCML) with a concomitant chronic lymphocytic leukemia (CLL)

Atypical chronic myeloid leukemia (aCML) is a rare hematological malignancy with dismal prognosis, usually being reported as isolated disease or in association with other myeloid neoplasms. Treatment strategies used for MDS and MPN, as hypomethylating agents (HMA) or kinase inhibitors, may be considered although experience is limited. We biologically studied an old patient affected by aCML unusually mutated for both SETBP1 and CSF3R, with concomitant chronic lymphocytic leukemia (CLL). Decitabine (DCA) therapy carried complete response after fourth cycle and was complicated by hematological toxicities and infections mainly due to the old age and the CLL-related immune deficit. Our case confirms DCA effectiveness in aCML and shows for the first time its safety even in older patients with concomitant lymphoproliferative disorders

Erratum: Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase (ACS Omega (2022) 7:20 (17083-17097) DOI: 10.1021/acsomega.2c00507)

(1) The following authors have been added: Ceìdric Schneider. Affiliations: Laboratoire Chimie Organique 2-Glycochimie, CNRS-UniversiteìClaude Bernard Lyon 1, Villeurbanne, France; Universiteì de Rouen, Mont-Saint- Aignan, France David Goyard. Affiliations: Laboratoire Chimie Organique 2-Glycochimie, CNRS-Universiteì Claude Bernard Lyon 1, Villeurbanne, France; Universiteì Grenoble Alpes, Grenoble, France Pierre Garcia. Affiliation: Laboratoire Chimie Organique 2- Glycochimie, CNRS-Universiteì Claude Bernard Lyon 1, Villeurbanne, France David Gueyrard. Affiliation: Laboratoire Chimie Organique 2-Glycochimie, CNRS-Universiteì Claude Bernard Lyon 1, Villeurbanne, France (2) In the third affiliation "Lyon, France"has been replaced by "Villeurbanne, France".These changes are reflected in the authorship of this Correction

De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways

Despite the advent of tyrosine kinase inhibitors, a proportion of chronic myeloid leukemia patients in chronic phase fails to respond to Imatinib or to second generation inhibitors and progress to blast crisis. Limited improvements in the understanding of the molecular mechanisms responsible for chronic myeloid leukemia transformation from chronic phase to the aggressive blast crisis were achieved until now. We present here a massive parallel sequencing analysis of 10 blast crisis samples and of the corresponding autologous chronic phase controls which reveals, for the first time, recurrent mutations affecting the ubiquitin-conjugating enzyme E2A gene (UBE2A, formerly RAD6A). Additional analyses on a cohort of 24 blast crisis, 41 chronic phase as well as 40 acute myeloid leukemia and 38 atypical chronic myeloid leukemia patients at onset confirmed that UBE2A mutations are specifically acquired during chronic myeloid leukemia progression with a frequency of 16.7% in advanced phases. In vitro studies show that the mutations here described cause a decrease in UBE2A activity, leading to an impairment of myeloid differentiation in chronic myeloid leukemia cells