Eric J Duncavage, Adam Bagg, Robert P Hasserjian, Courtney D DiNardo, Lucy A Godley, Ilaria Iacobucci, Siddhartha Jaiswal, Luca Malcovati, Alessandro M Vannucchi 9, Keyur P Patel, Daniel A Arber, Maria E Arcila, Rafael Bejar, Nancy Berliner, Michael J Borowitz, Susan Branford, Anna L Brown, Catherine A Cargo, Hartmut Döhner, Brunangelo Falini, Guillermo Garcia-Manero, Torsten Haferlach, Eva Hellström-Lindberg, Annette S Kim, Jeffery M Klco, Rami S Komrokji, Mignon L Loh, Sanam Loghavi, Charles G Mullighan, Seishi Ogawa, Ayalew Tefferi, Elli Papaemmanuil, Andreas Reiter, David Morrall Ross, Michael R Savona, Akiko Shimamura, Radek C Skoda, Francesc Sole, Richard M Stone, Attilio Orazi, Matthew J Walter, David Wu, Benjamin L Ebert, Mario Cazzola
Genomic Profiling for Clinical Decision Making in Myeloid Neoplasms and Acute Leukemia
Blood 21 Sep 2022, . Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. While assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the last several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole exome sequencing (WES), whole genome sequencing (WGS), and whole transcriptome sequencing (WTS) or RNAseq. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are employed not only for detecting somatically acquired gene mutations, but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias makes extensive use of genomic data. This report aims to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with these hematologic neoplasms.
Más informaciónCuartero S, Stik G, Stadhouders R
Three-dimensional genome organization in immune cell fate and function.
Nat Rev Immunol 20 Sep 2022, . Epub 20 Sep 2022Immune cell development and activation demand the precise and coordinated control of transcriptional programmes. Three-dimensional (3D) organization of the genome has emerged as an important regulator of chromatin state, transcriptional activity and cell identity by facilitating or impeding long-range genomic interactions among regulatory elements and genes. Chromatin folding thus enables cell type-specific and stimulus-specific transcriptional responses to extracellular signals, which are essential for the control of immune cell fate, for inflammatory responses and for generating a diverse repertoire of antigen receptor specificities. Here, we review recent findings connecting 3D genome organization to the control of immune cell differentiation and function, and discuss how alterations in genome folding may lead to immune dysfunction and malignancy.
Más informaciónPlana-Carmona M, Stik G, Bulteau R, Segura-Morales C, Alcázar N, Wyatt CDR, Klonizakis A, de Andrés-Aguayo L, Gasnier M, Tian TV, Torcal Garcia G, Vila-Casadesús M, Plachta N, Serrano M, Francesconi M, Graf T
The trophectoderm acts as a niche for the inner cell mass through C/EBPα-regulated IL-6 signaling.
Stem Cell Reports 13 Sep 2022, 17 (9) 1991-2004. Epub 11 Ago 2022IL-6 has been shown to be required for somatic cell reprogramming into induced pluripotent stem cells (iPSCs). However, how Il6 expression is regulated and whether it plays a role during embryo development remains unknown. Here, we describe that IL-6 is necessary for C/EBPα-enhanced reprogramming of B cells into iPSCs but not for B cell to macrophage transdifferentiation. C/EBPα overexpression activates both Il6 and Il6ra genes in B cells and in PSCs. In embryo development, Cebpa is enriched in the trophectoderm of blastocysts together with Il6, while Il6ra is mostly expressed in the inner cell mass (ICM). In addition, Il6 expression in blastocysts requires Cebpa. Blastocysts secrete IL-6 and neutralization of the cytokine delays the morula to blastocyst transition. The observed requirement of C/EBPα-regulated IL-6 signaling for pluripotency during somatic cell reprogramming thus recapitulates a physiologic mechanism in which the trophectoderm acts as niche for the ICM through the secretion of IL-6.
Más informaciónWinkler R, Mägdefrau AS, Piskor EM, Kleemann M, Beyer M, Linke K, Hansen L, Schaffer AM, Hoffmann ME, Poepsel S, Heyd F, Beli P, Möröy T, Mahboobi S, Krämer OH, Kosan C
Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition.
Oncogene 6 Sep 2022, . Epub 6 Sep 2022Overexpression of MYC is a genuine cancer driver in lymphomas and related to poor prognosis. However, therapeutic targeting of the transcription factor MYC remains challenging. Here, we show that inhibition of the histone deacetylase 6 (HDAC6) using the HDAC6 inhibitor Marbostat-100 (M-100) reduces oncogenic MYC levels and prevents lymphomagenesis in a mouse model of MYC-induced aggressive B-cell lymphoma. M-100 specifically alters protein-protein interactions by switching the acetylation state of HDAC6 substrates, such as tubulin. Tubulin facilitates nuclear import of MYC, and MYC-dependent B-cell lymphoma cells rely on continuous import of MYC due to its high turn-over. Acetylation of tubulin impairs this mechanism and enables proteasomal degradation of MYC. M-100 targets almost exclusively B-cell lymphoma cells with high levels of MYC whereas non-tumor cells are not affected. M-100 induces massive apoptosis in human and murine MYC-overexpressing B-cell lymphoma cells. We identified the heat-shock protein DNAJA3 as an interactor of tubulin in an acetylation-dependent manner and overexpression of DNAJA3 resulted in a pronounced degradation of MYC. We propose a mechanism by which DNAJA3 associates with hyperacetylated tubulin in the cytoplasm to control MYC turnover. Taken together, our data demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.
Más informaciónGuil S, Esteller M
PRC2 Loss and DNMT Inhibition Boost Viral Mimicry in Cancer.
Cancer Discov 2 Sep 2022, 12 (9) 2020-2022. In this issue of Cancer Discovery, Patel and colleagues explore the synergistic lethality of PRC2 inactivation and DNMT inhibition in malignant peripheral nerve sheath tumor cells. Reactivation of retrotransposons under this dual control suggests that the viral mimicry response contributes to enhanced cytotoxicity with potential clinical implications. See related article by Patel et al., p. 2120 (5).
Más información
