No abstract

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD leukemia cells. This synergized with the allogeneic CD8 T cell response, leading to long-term survival in six mouse models of FLT3-ITD AML. Sorafenib-related IL-15 production caused an increase in CD8CD107aIFN-γ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

Glioblastoma (GBM) is comprised of distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation. Here, ZBTB18 is primarily silenced in the mesenchymal subtype of GBM through aberrant promoter methylation. Loss of ZBTB18 contributes to the aggressive phenotype of glioblastoma through regulation of poor prognosis-associated signatures. Restitution of ZBTB18 expression reverses the phenotype and impairs tumor-forming ability. These results indicate that ZBTB18 functions as a tumor suppressor in GBM through the regulation of genes associated with phenotypically aggressive properties. Implications This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass.

The histopathological investigations of the esophageal wall in 17 patients undergoing esophageal resection or myotomy for achalasia suggest that the reduction of intramural ganglion cells might be a secondary change, probably due to inflammation triggered by autoimmune mechanisms or a chronic degenerative process of the central and/or peripheral part of the vagal nerve. The primary lesion could also be a severe myopathy of the smooth muscle cells.

For recurrent and untreatable meningiomas alternative therapies, such as anti-progesterone treatment, have been sought. However, the few clinical studies have not determined progesterone receptor (PgR) expression in most cases, and studies correlating quantitative PgR expression (PgR index) with clinico-pathological variables are scarce. The aim of our study was to assess the PgR indices in a consecutive series of meningiomas and correlate these values with clinico-pathological parameters. We analyzed immunohistochemically 82 consecutive meningioma specimens (73 primary and nine recurrent tumors) for PgR and Ki-67 antigen (MIB-1). The male/female ratio was 1:1.7, and median age at the time of surgery was 57 years (range 29-77 years). The series comprised 55 grade I (subtyped as 36 meningothelial, seven fibrous, nine transitional, two psammomatous, and one angiomatous), 23 grade II, and one grade III meningiomas. Nuclear immunostaining for PgR was positive in 56 meningioma specimens (71%). PgR index was 21.4+/-2.8% (mean +/- SE; range 0-79%). Significantly higher expression was found in male patients in the age group <50 years than in those > or = 60 years and in grade I meningothelial meningiomas than in fibrous and transitional subtypes. There was a trend to lower PgR indices in non-benign meningiomas. Cell proliferation rate (MIB-1 index) was 4.4 +/- 0.4% (mean +/- SE; range 0.3-15.4%). Significantly higher MIB-1 indices were found in male than female patients,in recurrent than primary and in grade II than grade I meningiomas. We observed a trend to higher PgR indices in meningiomas with MIB-1 index <5%. In sum, the highest PgR index in our series was observed in patients under the age of 50 years with WHO grade I meningiomas of the meningothelial subtype and low cell proliferation indices. If hormonal therapy has a direct action on the PgR, these patients should respond best to anti-progesterone treatment. We conclude that PgR index is variable in meningioma, depending on clinical parameters and histopathological features. Stratification of anti-progesterone therapy trials on the basis of PgR index should be considered.