Marriage and migration: Bengali and Bihari brides in Baduan, Uttar Pradesh

Shruti Chaudhry and Taneesha Mohan argue that cross-regional marriages in Uttar Pradesh do not constitute bride-buying or trafficking, and are instead a new kind of commercially mediated marriage

Lived experiences of marriage: regional and cross-regional brides in rural North India

Based on eleven months of ethnographic fieldwork (September 2012-August 2013) in a village in Baghpat district located in the western part of the north Indian state of Uttar Pradesh (UP), the thesis compares the lived experiences of marriage of women in what I describe as regional marriage (RM) with women in cross-regional marriage (CRM). RMs are marriages that conform to caste and community norms (caste endogamy, gotrā [clan] and village/territorial exogamy) and are negotiated within a limited geographical region, i.e., the state. CRMs are those between men in north India and women from the southern, eastern and north-eastern parts of the country. Such marriages cross caste, linguistic and state boundaries with the marriage distance exceeding 1000 kms. CRMs also differ from RMs with regard to their modes of arrangement and the payments involved. They result from two sets of factors – one operating at bride-sending regions (mainly poverty) and the other at bride-receiving regions (masculine sex ratios and the difficulties some men have in achieving “eligibility” for marriage). NGO and journalistic accounts and some academic work has focused on CRMs: being a consequence only of masculine sex ratios and bride shortages; deviating from north Indian marriage norms; involving the “sale” and “purchase” of poor women from poor districts and states; and CRBs’ low status and lack of agency in receiving communities. This research aims to interrogate the moral panic surrounding the “plight” of CRBs. The thesis begins by contextualising CRM by exploring the factors that lead some (UP) men of particular castes to seek brides from other states and those that influence the migration of women over long-distances for marriages. It examines the process of negotiation entailed in making a RM and a CRM – the role of matchmakers, marriage payments and the rituals regarded as necessary to make a marriage “legitimate”. The thesis then focuses on the question of lived experiences of marriage by examining different aspects of regional brides’ (RB) and cross-regional brides’ (CRB) everyday lives – what the process of adjustment in a new (marital) home means for women when they leave their natal homes to live in their husbands’ homes and villages, the work that married women do, their relationships with other women in their marital villages, their relationships with their husbands and with their natal kin. Married women’s lives are embedded in various power dynamics and this research aims to address how factors such as caste, class, religion and age/years of marriage shape women’s post-marital experiences, in addition to their regional origins. This ethnographic study also attempts to outline issues specific to CRBs, particularly discrimination, belonging and incorporation within a culturally and linguistically different context, as well as the intergenerational implications of these marriages in terms of the (caste) status, rights and marriages of children of cross-regional couples. This research departs from existing studies on CRM as it attempts to understand postmarital experiences through a comparison with RM. Such an approach makes it possible to recognise similarities in the lived experiences of RBs and CRBs that enables a more nuanced understanding of the gendering of intimate/marital relationships in contemporary rural India within a context of caste inequalities and poverty

Final technical report of the project on gender and migration : negotiating rights; a women’s movement perspective

The project devised a new method for assessing women’s work/employment situations through separation of paid and unpaid work, which has allowed for construction of a picture of female labour migration previously camouflaged in the official data by the dominance of marriage migration. At another level, the project investigated cross-region long distance marriage, to explore factors that determine movement of young brides to distant and different cultural regions. The research shows diverse patterns of migration and how migrant women workers are excluded from a range of citizenship rights: as migrant workers, as migrant women and as migrating citizens

Abstract P26: Altered RNA Export Sensitizes to Nuclear Export Inhibition in SF3B1 Mutant MDS

Abstract SF3B1 mutations, the most frequent spliceosomal alterations across cancers, occur in 25% of myelodysplastic syndromes (MDS) patients yet lack effective therapies. Two phase 2 clinical trials with the XPO1 inhibitors in high-risk MDS revealed increased activity in patients with SF3B1 mutations. XPO1 (Exportin-1) plays a role in the transport of multiple RNA species, including small nuclear RNAs (snRNAs) out of the nucleus. Given the role of XPO1 in exporting snRNAs, which form the catalytic portion of the spliceosome, we hypothesized that XPO1 inhibition may preferentially affect SF3B1-mutant cells and that SF3B1-mutant high-risk MDS patients would have a better response to rational targeted drug combinations with XPO1 inhibitors. To evaluate the mechanism underlying the preferential sensitivity of SF3B1-mutant cells to XPO1 inhibition, we conducted subcellular RNA sequencing before and after XPO1 inhibition in SF3B1 wildtype and mutant cells. Transcriptomic analysis revealed increased global retention of RNA transcripts and elevated snRNAs in the nucleus after XPO1 inhibition in the SF3B1 mutant cell line. Global RNA expression and splicing analysis revealed increased alternative splicing in SF3B1 mutant cells after XPO1 inhibition. These results suggest that the preferential sensitivity of SF3B1 mutant cells to nuclear export inhibition arises through increased nuclear retention of spliceosomal snRNAs and select mRNAs that results in perturbation of apoptotic pathways. Despite the promising efficacy of XPO1 inhibition in SF3B1-mutated MDS, dose escalation is limited by toxicity. In order to identify novel drug combination targets with lower XPO1 inhibitor doses, we employed whole genome CRISPR screens in two acute myeloid leukemia (AML) cell lines treated with XPO1 inhibitor. We identified two drug targets that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and A1331852 (a BCL-XL inhibitor). In addition, BH3 profiling demonstrated increased priming of the BCL2 and BCL-XL in SF3B1 mutant cells. We further validated these combinations in vivo using competitive transplant assays in Sf3b1 K700E conditional knock-in mice. The combination of eltanexor with venetoclax and eltanexor with A1331852 showed a significant decrease in the Sf3b1-mutant burden in the peripheral blood and bone marrow progenitor compartments, suggesting a preferential sensitivity of the combinations for SF3B1 mutant cells. Although A1331852 exhibited similar results to venetoclax, there was increased weight loss and decrease in hemoglobin associated with BCLXL inhibition. In conclusion, our study provides insight on the mechanisms underlying the heightened sensitivity of XPO1 inhibition in SF3B1-mutant MDS/AML. The identification of BCL2 and BCL-XL as synergistic targets with XPO1 inhibitors, validated by in vivo testing, BH3 profiling, and RNA sequencing, highlights the potential for therapeutic combinations. Specifically, the combination of eltanexor and venetoclax could be a promising SF3B1-specific therapy. Citation Format: Sana Chaudhry, Felipe Beckedorff, Shaista Shabbir Jasdanwala, Tulasigeri M Totiger, Maurizio Affer, Nidhi Hariramani, Olivia Tonini, Stephan Noudali, Alexandra Chirino, Alyssa Cornista, Skye Montoya, Daniel Bilbao, Jumana Afaghani, Jose Antonio Rodríguez, Shruti Bhatt, Eric Wang, Justin Taylor. Altered RNA Export Sensitizes to Nuclear Export Inhibition in SF3B1 Mutant MDS [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P26

Altered RNA export by SF3B1 mutants confers sensitivity to nuclear export inhibition

SF3B1 mutations frequently occur in cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic pathways. To identify novel drug combinations that synergize with XPO1 inhibition, a forward genetic screen was performed with eltanexor treatment implicating anti-apoptotic targets BCL2 and BCLXL, which were validated by functional testing in vitro and in vivo. These targets were tested in vivo using Sf3b1K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS.SF3B1 mutations frequently occur in cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic pathways. To identify novel drug combinations that synergize with XPO1 inhibition, a forward genetic screen was performed with eltanexor treatment implicating anti-apoptotic targets BCL2 and BCLXL, which were validated by functional testing in vitro and in vivo. These targets were tested in vivo using Sf3b1K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS