PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression.

Our study explores the complex dynamics of the integrated stress response (ISR) axis, highlighting PIM2 kinase's critical role and its interaction with the BCL2 protein family, uncovering key mechanisms of cell survival and tumor progression. Elevated PIM2 expression, a marker of various cancers, often correlates with disease aggressiveness. Using a model of normal and malignant plasma cells, we show that inhibiting PIM2 kinase inhibits phosphorylated BAD production and activates ISR-mediated NOXA expression.

Single-hit genome editing optimized for maturation in B cells redirects their specificity toward tumor antigens.

T-cell-based adoptive immunotherapy is a new pillar of cancer care. Tumor-redirected B cells could also contribute to therapy if their manipulation to rewire immunoglobulin (Ig) genes is mastered. We designed a single-chain Ig-encoding cassette ("scFull-Ig") that redirects antigen specificity when inserted at a single position of the IgH locus.

CD38, CD39, and BCL2 differentiate disseminated forms of high-grade B-cell lymphomas in biological fluids from Burkitt lymphoma and diffuse large B-cell lymphoma.

High-grade B-cell lymphomas (HGBCL) represent a heterogeneous group of very rare mature B-cell lymphomas. The 4th revised edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (WHO-HAEM) previously defined two categories of HGBCL: the so-called double-hit (DHL) and triple-hit (THL) lymphomas, which were related to forms harboring MYC and BCL2 and/or BCL6 rearrangements, and HGBCL, NOS (not otherwise specified), corresponding to entities with intermediate characteristics between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL), without rearrangement of the MYC and BCL2, and/or BCL6 genes. In the 5th edition of the WHO-HAEM, DHL with MYC and BCL2 rearrangements or THL were reassigned as DLBCL/HGBCL with MYC and BCL2 rearrangements (DLBCL/HGBL-MYC/BCL2), whereas the category HGBCL, NOS remains unchanged.

BHLHE41, a transcriptional repressor involved in physiological processes and tumor development.

BHLHE41 is a nuclear transcriptional repressor that belongs to the basic helix-loop-helix protein superfamily. BHLHE41 expression tends to be restricted to specific tissues and is regulated by environmental cues and biological events. BHLHE41 homodimerizes or heterodimerizes with various partners, influencing its transcription factor function.

F158V alleles frequency differs in multiple myeloma patients from healthy population.

presents a single nucleotide polymorphism at location 158 (V/F), which affects its binding to the fragment crystallizable (Fc) of antibodies (Abs). FcγRIIIa-158 V allotype has the highest affinity and is associated with a better clinical response to IgG1 monoclonal Abs (mAb) treatment. We compared the allele frequency of F158V polymorphism in cohorts of patients with B-cell lymphoproliferative disorders, including multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), non-Hodgkin lymphoma (NHL), and B-cell chronic leukemia (B-CLL).

Quantitative Integrative Survival Prediction in Multiple Myeloma Patients Treated With Bortezomib-Based Induction, High-Dose Therapy and Autologous Stem Cell Transplantation.

Purpose: Given the high heterogeneity in survival for patients with multiple myeloma, it would be clinically useful to quantitatively predict the individual survival instead of attributing patients to two to four risk groups as in current models, for example, revised International Staging System (R-ISS), R2-ISS, or Mayo-2022-score.

Patients And Methods: Our aim was to develop a quantitative prediction tool for individual patient's 3-/5-year overall survival (OS) probability. We integrated established clinical and molecular risk factors into a comprehensive prognostic model and evaluated and validated its risk discrimination capabilities versus R-ISS, R2-ISS, and Mayo-2022-score.

MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling.

Oncogene-induced senescence (OIS) arrests cell proliferation in response to replication stress (RS) induced by oncogenes. OIS depends on the DNA damage response (DDR), but also on the cGAS-STING pathway, which detects cytosolic DNA and induces type I interferons (IFNs). Whether and how RS and IFN responses cooperate to promote OIS remains unknown.

Transient loss of Polycomb components induces an epigenetic cancer fate.

Although cancer initiation and progression are generally associated with the accumulation of somatic mutations, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility, suggesting that genetic mechanisms might not be the only drivers of malignant transformation. However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations has been unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila.

Integrative single-cell chromatin and transcriptome analysis of human plasma cell differentiation.

Plasma cells (PCs) are highly specialized cells representing the end stage of B-cell differentiation. We have shown that PC differentiation can be reproduced in vitro using elaborate culture systems. The molecular changes occurring during PC differentiation are recapitulated in this in vitro differentiation model.

Combined inhibition of Wee1 and Chk1 as a therapeutic strategy in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents that have significantly improved clinical outcome, most patients relapse and develop drug resistance. MM is characterized by genomic instability and a high level of replicative stress.

Immunophenotypic portrait of leukemia-associated-phenotype markers in B acute lymphoblastic leukemia.

Background: Multiparametric flow cytometry (MFC) is an essential diagnostic tool in B acute lymphoblastic leukemia (B ALL) to determine the B-lineage affiliation of the blast population and to define their complete immunophenotypic profile. Most MFC strategies used in routine laboratories include leukemia-associated phenotype (LAP) markers, whose expression profiles can be difficult to interpret. The aim of our study was to reach a better understanding of 7 LAP markers' landscape in B ALL: CD9, CD21, CD66c, CD58, CD81, CD123, and NG2.

RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma.

Background: Immunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of available compounds, strategies for appropriate choice of targets (combinations) are warranted. Simultaneously, risk assessment is advisable as patient's life expectancy varies between months and decades.

S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability in multiple myeloma.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy and is incurable because of the inevitable development of drug resistance. Methionine adenosyltransferase 2α (MAT2A) is the primary producer of the methyl donor S-adenosylmethionine (SAM) and several studies have documented MAT2A deregulation in different solid cancers. As the role of MAT2A in MM has not been investigated yet, the aim of this study was to clarify the potential role and underlying molecular mechanisms of MAT2A in MM, exploring new therapeutic options to overcome drug resistance.

Var∣Decrypt: a novel and user-friendly tool to explore and prioritize variants in whole-exome sequencing data.

Background: High-throughput sequencing (HTS) offers unprecedented opportunities for the discovery of causative gene variants in multiple human disorders including cancers, and has revolutionized clinical diagnostics. However, despite more than a decade of use of HTS-based assays, extracting relevant functional information from whole-exome sequencing (WES) data remains challenging, especially for non-specialists lacking in-depth bioinformatic skills.

Results: To address this limitation, we developed Var∣Decrypt, a web-based tool designed to greatly facilitate WES data browsing and analysis.

3-O sulfation of syndecan-1 mediated by the sulfotransferase HS3ST3a1 enhances myeloma aggressiveness.

Multiple myeloma is a hematological neoplasm derived from plasma cells invariably developing in the bone marrow (BM). The persisting clinical challenge in MM resides in its high ability to resist drugs as shown by the frequent relapses observed in patients regardless of the treatment applied. In a mouse model of MM, we identified a subpopulation of cells harboring increased resistance to current MM drugs.

The BLM helicase is a new therapeutic target in multiple myeloma involved in replication stress survival and drug resistance.

Multiple myeloma (MM) is a hematologic cancer characterized by accumulation of malignant plasma cells in the bone marrow. To date, no definitive cure exists for MM and resistance to current treatments is one of the major challenges of this disease. The DNA helicase BLM, whose depletion or mutation causes the cancer-prone Bloom's syndrome (BS), is a central factor of DNA damage repair by homologous recombination (HR) and genomic stability maintenance.

LAIR1, an ITIM-Containing Receptor Involved in Immune Disorders and in Hematological Neoplasms.

Leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1, CD305) belongs to the family of immune-inhibitory receptors and is widely expressed on hematopoietic mature cells, particularly on immune cells. Four different types of ligands of LAIR1 have been described, including collagens, suggesting a potential immune-regulatory function on the extracellular matrix. By modulating cytokine secretion and cellular functions, LAIR1 displays distinct patterns of expression among NK cell and T/B lymphocyte subsets during their differentiation and cellular activation and plays a major negative immunoregulatory role.

Targeting the β -adrenergic receptor increases chemosensitivity in multiple myeloma by induction of apoptosis and modulating cancer cell metabolism.

While multi-drug combinations and continuous treatment have become standard for multiple myeloma, the disease remains incurable. Repurposing drugs that are currently used for other indications could provide a novel approach to improve the therapeutic efficacy of standard multiple myeloma treatments. Here, we assessed the anti-tumor effects of cardiac drugs called β-blockers as a single agent and in combination with commonly used anti-myeloma therapies.