HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib

Activating mutations in MYD88 are present in approximately 95% of patients with Waldenstrom Macroglobulinemia (WM), as well as other B-cell malignancies including ABC DLBCL. In WM, mutated MYD88 triggers activation of BTK. Ibrutinib, a pleiotropic kinase inhibitor that targets BTK, is highly active in patients with mutated MYD88. We observed that mutated MYD88 WM and ABC DLBCL cell lines, as well as primary WM cells show enhanced HCK transcription and activation, and that HCK is activated by IL6. Over-expression of mutated MYD88 triggers HCK and IL6 transcription, while knockdown of HCK reduced survival and attenuated BTK, PI3K/AKT, and MAPK/ERK signaling in mutated MYD88 WM and/or ABC DLBCL cells. Ibrutinib and the more potent HCK inhibitor A419259 blocked HCK activation and induced apoptosis in mutated MYD88 WM and ABC DLBCL cells. Docking and pull-down studies confirmed that HCK was a target of ibrutinib. Ibrutinib and A419259 also blocked ATP binding to HCK, while transduction of mutated MYD88 expressing WM cells with a mutated HCK gatekeeper greatly increased the EC50 for ibrutinib and A419259. The findings support that HCK expression and activation is triggered by mutated MYD88, supports the growth and survival of mutated MYD88 WM and ABC DLBCL cells, and is a direct target of ibrutinib. HCK represents a novel target for therapeutic development in MYD88 mutated WM and ABC DLBCL, and possibly other diseases driven by mutated MYD88

A fine balancing act:a delicate kinase-phosphatase equilibrium that protects against chromosomal instability and cancer

Cancer cells rewire signalling networks to acquire specific hallmarks needed for their proliferation, survival, and dissemination throughout the body. Although this is often associated with the constitutive activation or inactivation of protein phosphorylation networks, there are other contexts when the dysregulation must be much milder. For example, chromosomal instability is a widespread cancer hallmark that relies on subtle defects in chromosome replication and/or division, such that these processes remain functional, but nevertheless error-prone. In this article, we will discuss how perturbations to the delicate kinase-phosphatase balance could lie at the heart of this type of dysregulation. In particular, we will explain how the two principle mechanisms that safeguard the chromosome segregation process rely on an equilibrium between at least two kinases and two phosphatases to function correctly. This balance is set during mitosis by a central complex that has also been implicated in chromosomal instability – the BUB1/BUBR1/BUB3 complex – and we will put forward a hypothesis that could link these two findings. This could be relevant for cancer treatment because most tumours have evolved by pushing the boundaries of chromosomal instability to the limit. If this involves subtle changes to the kinase-phosphatase equilibrium, then it may be possible to exacerbate these defects and tip tumour cells over the edge, whilst still maintaining the viability of healthy cells

Dans les remous de la mémoire / Yvon Bohers

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cfDNA Sequencing: Technological Approaches and Bioinformatic Issues

International audienceIn the era of precision medicine, it is crucial to identify molecular alterations that will guide the therapeutic management of patients. In this context, circulating tumoral DNA (ctDNA) released by the tumor in body fluids, like blood, and carrying its molecular characteristics is becoming a powerful biomarker for non-invasive detection and monitoring of cancer. Major recent technological advances, especially in terms of sequencing, have made possible its analysis, the challenge still being its reliable early detection. Different parameters, from the pre-analytical phase to the choice of sequencing technology and bioinformatic tools can influence the sensitivity of ctDNA detection

cfDNA Sequencing: Technological Approaches and Bioinformatic Issues

In the era of precision medicine, it is crucial to identify molecular alterations that will guide the therapeutic management of patients. In this context, circulating tumoral DNA (ctDNA) released by the tumor in body fluids, like blood, and carrying its molecular characteristics is becoming a powerful biomarker for non-invasive detection and monitoring of cancer. Major recent technological advances, especially in terms of sequencing, have made possible its analysis, the challenge still being its reliable early detection. Different parameters, from the pre-analytical phase to the choice of sequencing technology and bioinformatic tools can influence the sensitivity of ctDNA detection.</jats:p