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Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935–47. ©2018 AACR.

This file contains additional data related to the results shown in figures 1-5 of the main manuscript.

This table contains antibody information and primer sequences.

This file contains detailed information on the mass spectrometry approach.

Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy. Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935–47. ©2018 AACR.

Objectives. FMF is characterized by recurrent self-limiting episodes of fever and painful polyserositis. We aimed to study the spectrum and distribution of MEFV mutations in an Algerian patient cohort using a comprehensive mutation detection method. Using the same methodology, we also studied the carrier rate in an unaffected ethnically matched control cohort. Methods. We recruited 71 unrelated subjects clinically diagnosed with FMF from various clinics in the central region of Algeria. Two hundred and thirty control subjects were recruited as well. Mutation detection in MEFV was performed by re-sequencing the promoter region, the entire coding sequence and all exonintron boundaries. Results. We detected eight different mutations located in exons 10 (p.M694I, p.M694V, p.A744S, p.M680I, p.I692Del), 9 (p.I591T), 3 (p.P369S/p.R408Q) and 2 (p.E148Q). Out of the 71 patients, 31 carried at least one mutation. While the 71 patients are expected to have 142 mutant chromosomes, only 50 were identified. p.M694I (17.6%) is the most common mutation, followed by p.M694V (5%), p.E148Q (4.2%), p.A744S (3.5%) and p.M680I (3%). One novel variant was identified in the promoter region in the heterozygous state in three patients and in two controls. The carrier rate of the identifiable mutations is estimated to be 1 : 5. Conclusion. This study describes the MEFV mutational spectrum and distribution in the Algerian population. It shows that p.M694I is the most common MEFV mutation in Algerians. It also shows that, similar to other Arabic populations

Background: Autoinflammatory diseases are a group of disorders characterized by seemingly unprovoked inflammation in the absence of high-titer autoantibodies or antigen-specific T cells. Familial Mediterranean Fever (FMF) is an autosomal recessive disorder. It is characterized by recurrent self-limiting episodes of fever and painful polyserositis. FMF is prevalent in specific ethnic groups—namely, non-Ashkenazi Jews, Armenians, Turks, and Arabs. There seems to be a distinctive clinical picture in Arab patients with FMF, and the range and distribution of MEFV mutations is different from that noted in other commonly affected ethnic groups. Objectives: The aim of this study is to delineate the spectrum and distribution of MEFV mutations amongst an Arabic FMF patient cohort and to assist the genotype-phenotype correlation in these patients. Methods: We have collected DNA samples from 188 FMF patients (from Qatar, Jordan and Palestine) who have been clinically diagnosed with FMF, according to internat...