Climate, conflict and internal migration in Colombia

Robust empirical evidence on the potential causal linkages between environmental change, conflict and migration is scarce. We evaluate this relationship in the context of internal migration in Colombia for the period from 2000 to 2005. Using municipalitylevel data in a gravity model that considers the issue of endogenous selection regarding both the outbreak of conflicts and the existence of non-zero migration flows, we establish an empirical causal link between droughts, conflict and migration. Our results show a positive relationship between the severity of droughts and the likelihood of conflicts, as well as between conflicts and human mobility, suggesting an indirect effect of climate on internal migration in Colombia

Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.This work was supported by a research grant from the Deutsche Krebshilfe (Mildred Scheel Professur) and the Wilhelm Sander-Stiftung to CD Baldu

mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph +

Elevated activity of mTOR is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high-risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph+ and Ph-like B-ALL models. Surprisingly, inhibiting mTOR complex 1 (mTORC1) protected B-ALL cells from killing by methotrexate and 6-mercaptopurine, two antimetabolite drugs used in maintenance chemotherapy. The cytoprotective effects correlated with decreased cell-cycle progression and were recapitulated using cell-cycle inhibitors, palbociclib or aphidicolin. Dasatinib, a tyrosine kinase inhibitor currently used in Ph+ patients, inhibits ABL kinase upstream of mTOR. Dasatinib resistance is mainly caused by ABL kinase mutations, but is also observed in a subset of ABL unmutated cases. We identified dasatinib-resistant Ph+ cell lines and patient samples in which dasatinib can effectively reduce ABL kinase activity and mTORC1 signaling without causing cell death. In these cases, dasatinib protected leukemia cells from killing by 6-mercaptopurine. Using xenograft models, we observed that mTOR inhibition or dasatinib increased the numbers of leukemia cells that emerge after cessation of chemotherapy treatment. These results demonstrate that inhibitors targeting mTOR or upstream signaling nodes should be used with caution when combined with chemotherapeutic agents that rely on cell-cycle progression to kill B-ALL cells. Mol Cancer Ther; 16(9); 1942-53. ©2017 AACR

Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL

Abstract Background GATA3 is pivotal for the development of T lymphocytes. While its effects in later stages of T cell differentiation are well recognized, the role of GATA3 in the generation of early T cell precursors (ETP) has only recently been explored. As aberrant GATA3 mRNA expression has been linked to cancerogenesis, we investigated the role of GATA3 in early T cell precursor acute lymphoblastic leukemia (ETP-ALL). Methods We analyzed GATA3 mRNA expression by RT-PCR (n = 182) in adult patients with T-ALL. Of these, we identified 70 of 182 patients with ETP-ALL by immunophenotyping. DNA methylation was assessed genome wide (Illumina Infinium® HumanMethylation450 BeadChip platform) in 12 patients and GATA3-specifically by pyrosequencing in 70 patients with ETP-ALL. The mutational landscape of ETP-ALL with respect to GATA3 expression was investigated in 18 patients and validated by Sanger sequencing in 65 patients with ETP-ALL. Gene expression profiles (Affymetrix Human genome U133 Plus 2.0) of an independent cohort of adult T-ALL (n = 83) were used to identify ETP-ALL and investigate GATA3low and GATA3high expressing T-ALL patients. In addition, the ETP-ALL cell line PER-117 was investigated for cytotoxicity, apoptosis, GATA3 mRNA expression, DNA methylation, and global gene expression before and after treatment with decitabine. Results In our cohort of 70 ETP-ALL patients, 33 % (23/70) lacked GATA3 expression and were thus defined as GATA3low. DNA methylation analysis revealed a high degree of GATA3 CpG island methylation in GATA3low compared with GATA3high ETP-ALL patients (mean 46 vs. 21 %, p < 0.0001). Genome-wide expression profiling of GATA3low ETP-ALL exhibited enrichment of myeloid/lymphoid progenitor (MLP) and granulocyte/monocyte progenitor (GMP) genes, while T cell-specific signatures were downregulated compared to GATA3high ETP-ALL. Among others, FLT3 expression was upregulated and mutational analyses demonstrated a high rate (79 %) of FLT3 mutations. Hypomethylating agents induced reversal of GATA3 silencing, and gene expression profiling revealed downregulation of hematopoietic stem cell genes and upregulation of T cell differentiation. Conclusions We propose GATA3low ETP-ALL as a novel stem cell-like leukemia with implications for the use of myeloid-derived therapies

Additional file 4: Figure S3. of Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL

GATA3 expression in human leukemia cell lines. (A) RT-PCR-based analysis of GATA3 mRNA expression relative to Jurkat indicates differential GATA3 mRNA expression. (B) Western blot analysis revealed differential GATA3 protein expression (predicted molecular weight of 47 kDa). (JPG 35 kb

Additional file 10: Table S4. of Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL

KEGG pathway annotation of DEG in PER-117 cells before versus after treatment with decitabine. Lists of 1.5-fold over- and underexpressed genes of cells treated with decitabine (5 ΟM) were uploaded to DAVID Bioinformatics Resources v6.7. Listed are selected KEGG annotated pathway elements significantly enriched in cells treated with decitabine. (PNG 61 kb

Additional file 7: Figure S5. of Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL

The GATA3low gene expression profile identified cases with ETP-ALL in an independent cohort of T-ALL. Unsupervised hierarchical cluster analysis of diagnostic bone marrow samples from 55 pediatric patients with T-ALL, using a set of genes defined by low GATA3 expression in adult T-ALL. Classification of ETP-ALL and non-ETP-ALL was performed according to the ETP gene expression signature published along with this dataset. (PNG 484 kb

Additional file 3: Figure S2. of Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL

PER-117 and Loucy are ETP-ALL cell lines. Hierarchical clustering of ETP-ALL and non-ETP-ALL cell lines, using a set of genes differentially expressed in pediatric patients with ETP-ALL compared with non-ETP-ALL [20]. (PNG 63 kb