The MLL-Menin Interaction is a Therapeutic Vulnerability in <em>NUP98</em>-rearranged AML

\ua9 2023 Wolters Kluwer Health. All rights reserved. Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin-MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors

Containing, embracing and hyper-activating Britishness: British-based foreign-owned firms

There are in the UK ownership forms different to the characteristics of Britishness – British-based foreign-owned firms where dominant owners may have differentiated control interests. These may contain, that is, override, national institutional characteristics embedded in a particular national capitalism. Accordingly, separating the agency of these firms from presumed business system structures may reveal how diverse patterns of firm ownership – those associated with British-based foreign-owned firms – can inform dynamic ownership developments in British capitalism which contain and hyper-activate Britishness. The article theorizes British-based foreign-owned firms and provides empirical detail on how ownership characteristics influence financial commitment and strategic control in 10 of these firms

The effects of financialisation and financial development on investment: Evidence from firm-level data in Europe

In this paper we estimate the effects of financialization on physical investment in selected western European countries using panel data based on the balance-sheets of publicly listed non-financial companies (NFCs) supplied by Worldscope for the period 1995-2015. We find robust evidence of an adverse effect of both financial payments (interests and dividends) and financial incomes on investment in fixed assets by the NFCs. This finding is robust for both the pool of all Western European firms and single country estimations. The negative impacts of financial incomes are non-linear with respect to the companies’ size: financial incomes crowd-out investment in large companies, and have a positive effect on the investment of only small, relatively more credit-constrained companies. Moreover, we find that a higher degree of financial development is associated with a stronger negative effect of financial incomes on companies’ investment. This finding challenges the common wisdom on ‘finance-growth nexus’. Our findings support the ‘financialization thesis’ that the increasing orientation of the non-financial sector towards financial activities is ultimately leading to lower physical investment, hence to stagnant or fragile growth, as well as long term stagnation in productivity

Consumer credit in comparative perspective

We review the literature in sociology and related fields on the fast global growth of consumer credit and debt and the possible explanations for this expansion. We describe the ways people interact with the strongly segmented consumer credit system around the world—more specifically, the way they access credit and the way they are held accountable for their debt. We then report on research on two areas in which consumer credit is consequential: its effects on social relations and on physical and mental health. Throughout the article, we point out national variations and discuss explanations for these differences. We conclude with a brief discussion of the future tasks and challenges of comparative research on consumer credit.Accepted manuscrip

Corporate governance and inequality: The impact of financialization and shareholder value

Copyright © 2017 by Emerald Group Publishing Limited. Purpose - The purpose of this chapter is to analyse how in recent years the rediscovery that extreme inequality is returning to advanced economies and has become widespread. What is at issue are the causes of this inequality. It is becoming clear that the wider population, particularly in Anglo-American economies have not shared in the growing wealth of the countries concerned, and that the majority of this wealth is being transferred on a continuous and systemic basis to the very rich. Corporate governance and the pursuit of shareholder value it is argued has become a major driver of inequality. Methodology/approach - The current statistical evidence produced by leading authorities including the US Federal Reserve, World Economic Forum, Credit Suisse and Oxfam are examined. The policy of shareholder value and the mechanisms by which the distributions from business take place are investigated from a critical perspective. Findings - While the Anglo-American economies are seeing a return to the extremes of inequality last witnessed in the 19th century, the causes of this inequality are changing. In the 19th century great fortunes often were inherited, or derived by entrepreneurs from the ownership and control of productive assets. By the late 20th century as Atkinson, Piketty and Saez (2011) and others have highlighted, the sustained and rapid inflation in top income shares have made a significant contribution to the accelerating rate of income and wealth inequality. Research implications - The intensification of inequality in advanced industrial economies, despite the consistent work of Atkinson and others, was largely neglected until the recent research of Picketty which has attracted international attention. It is now acknowledged widely that inequality is a serious issue; however, the contemporary causes of inequality remain largely unexplored. Practical/social implications - The significance of inequality, now that it is recognized, demands policy and practical interventions. However, the capacity or even willingness to intervene is lacking. Further analysis of the debilitating consequences of inequality in terms of the efficiency and stability of economies and societies may encourage a more robust approach, yet the resolve to end extreme inequality is not present. Originality/value - The analysis of inequality has not been neglected and this chapter represents a pioneering effort to relate the shareholder value orientation now dominant in corporate governance to the intensification of inequality

Disarticulation and the Crisis of Neoliberalism in the United States

Neoliberal policies instituted since the 1980s have transformed the United States economy in ways that have produced serious structural distortions in the basic operation of capitalism. Using Samir Amin’s concept of disarticulation, previously applied exclusively to the periphery of the world economy, this article argues that the twin and mutually reinforcing features of neoliberalism – global corporate restructuring and financialization – have now generated disarticulation in the core nations. This disarticulated structure is responsible for the economic stagnation and sharply unequal income/wealth distributional outcomes that characterize contemporary U.S. capitalism

Calculability as politics in the construction of markets: the case of socially responsible investment in France

This paper examines some of the processes by which power constitutes calculability and, in so doing, shapes the construction of markets. We combine insights from performativity studies about calculability with Lukes’ ‘radical view of power’ to investigate how multiple facets of power are mobilized to influence the creation and activities of calculative agencies in the process of market construction. An in-depth longitudinal study of the French socially responsible investment market shows how organizations acting as calculative agencies become sites of power through calculability. We identify how power is exercised over, through and against these calculative agencies by a variety of actors in order to build their position in the socially responsible investment market. Our results complement the broader question of the ‘government of economic life’ by showing how micro-level power games interact with the macro-politics of market building through calculative agencies. In so doing, our paper sheds light on neglected aspects of the changing geopolitics of calculative power in market construction and suggests approaching ‘calculability as politics’ when studying the construction of markets

The financialization of the non‐financial corporation. A critique to the financial turn of accumulation hypothesis

One aspect in which non-financial corporations (NFCs) are said to be financialized is that they have been increasingly engaged in financial accumulation from which they derive a growing proportion of financial income. This is what we call the financial turn of accumulation hypothesis. In this article, we show that the evidence used to sustain it, in the U.S. setting, has to be reconsidered. Our findings show that, contrary to the financial turn of accumulation hypothesis, financial income averages 2.5% of NFCs’ total income since the 1980s, oscillating since the beginnings of the 1990s until 2005 and then declining. In terms of assets, some of the alleged financial assets might actually reflect other activities in which NFCs have been increasingly engaged, such as tax avoidance, internationalization of production, activities refocusing and M&As