ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development.

Alterations inactivating the tumor suppressor gene PTEN drive the development of solid and hematologic cancers, such as T-cell acute lymphoblastic leukemia (T-ALL), in which phosphatase and tensin homolog (PTEN) loss defines poor-prognosis patients. We investigated the metabolic rewiring induced by PTEN loss in T-ALL, aiming to identify novel metabolic vulnerabilities. We showed that the enzyme adenosine triphosphate (ATP) citrate lyase (ACLY) is strictly required for the transformation of thymic immature progenitors and the growth of human T-ALL, which remain dependent on ACLY activity even upon transformation.

Optimizing drug combinations for T-PLL: restoring DNA damage and P53-mediated apoptotic responses.

T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, that is, the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL's pathobiology fostered the identification of actionable vulnerabilities: (1) altered epigenetics, (2) defective DNA damage responses, (3) aberrant cell-cycle regulation, and (4) deregulated prosurvival pathways, including T-cell receptor and JAK/STAT signaling.

A novel inhibitor of the mitochondrial respiratory complex I with uncoupling properties exerts potent antitumor activity.

Cancer cells are highly dependent on bioenergetic processes to support their growth and survival. Disruption of metabolic pathways, particularly by targeting the mitochondrial electron transport chain complexes (ETC-I to V) has become an attractive therapeutic strategy. As a result, the search for clinically effective new respiratory chain inhibitors with minimized adverse effects is a major goal.

Exogenous IL-2 delays memory precursors generation and is essential for enhancing memory cells effector functions.

To investigate the impact of paracrine IL-2 signals on memory precursor (MP) cell differentiation, we activated CD8 T cell in the presence or absence of exogenous IL-2 (ex-IL-2). We assessed memory differentiation by transferring these cells into virus-infected mice. Both conditions generated CD8 T cells that participate in the ongoing response and gave rise to similar memory cells.

Functional precision oncology for follicular lymphoma with patient-derived xenograft in avian embryos.

Despite achieving high rates of complete remission with RCHOP immuno-chemotherapy, almost all patients with follicular lymphoma (FL) will experience multiple relapses after treatment. The lack of experimental model of FL limits our understanding of heterogeneity in treatment response. Here we characterized a new model of FL patient-derived xenograft (PDX) in avian embryos.

KIR3DL2 contributes to the typing of acute adult T-cell leukemia and is a potential therapeutic target.

Adult T-cell leukemia (ATL) is a lymphoid neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), which encodes the transcriptional activator Tax, which participates in the immortalization of infected T cells. ATL is classified into 4 subtypes: smoldering, chronic, acute, and lymphoma. We determined whether natural killer receptors (NKRs) were expressed in ATL.

Development of thymic tumor in [LSL:Kras; Pdx1-CRE] mice, an adverse effect associated with accelerated pancreatic carcinogenesis.

Pancreatic Ductal AdenoCarcinoma (PDAC) represents about 90% of pancreatic cancers. It is one of the most aggressive cancer, with a 5-year survival rate below 10% due to late diagnosis and poor therapeutic efficiency. This bad prognosis thus encourages intense research in order to better understand PDAC pathogenesis and molecular basis leading to the development of innovative therapeutic strategies.

Plasticity of Mature B Cells Between Follicular and Classic Hodgkin Lymphomas: A Series of 22 Cases Expanding the Spectrum of Transdifferentiation.

Follicular lymphoma and classic Hodgkin lymphoma can be associated in composite and/or sequential lymphomas. Common IGH and BCL2 rearrangements have already been identified between both contingents of these entities, but mutation profiles have not yet been investigated. The main objective of this study was to analyze the transdifferentiation process that may occur between Hodgkin and follicular contingents in sequential and composite lymphomas to better characterize these entities.

Characteristics of T- and NK-cell Lymphomas After Renal Transplantation: A French National Multicentric Cohort Study.

Background: Posttransplant lymphoproliferative disorders (PTLDs) encompass a spectrum of heterogeneous entities. Because the vast majority of cases PTLD arise from B cells, available data on PTLD of T or NK phenotype (T/NK-cell PTLD) are scarce, which limits the quality of the management of these patients.

Methods: All adult cases of PTLD diagnosed in France were prospectively recorded in the national registry between 1998 and 2007.

Zeb1 represses TCR signaling, promotes the proliferation of T cell progenitors and is essential for NK1.1 T cell development.

T cell development proceeds under the influence of a network of transcription factors (TFs). The precise role of Zeb1, a member of this network, remains unclear. Here, we report that Zeb1 expression is induced early during T cell development in CD4CD8 double-negative (DN) stage 2 (DN2).

Development of a Model for Chemical Screening Based on Collateral Sensitivity to Target BTK C481S Mutant.

Targeted therapies have improved the outcome of cancer, but their efficacy is intrinsically limited by the emergence of subclones with a mutation in the gene encoding the target protein. A few examples of collateral sensitivity have demonstrated that the conformational changes induced by these mutations can create unexpected sensitivity to other kinase inhibitors, but whether this concept can be generalized is unknown. Here is described the development of a model to screen a library of kinase inhibitors for collateral sensitivity drugs active on the Bruton Tyrosine Kinase (BTK) protein with the ibrutinib resistance mutation C481S.

GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism.

GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL).

[Even the Warburg effect can be oxidized: metabolic cooperation and tumor development].

During tumor development, malignant cells rewire their metabolism to meet the biosynthetic needs required to increase their biomass and to overcome their microenvironment constraints. The sustained activation of aerobic glycolysis, also called Warburg effect, is one of these adaptative mechanisms. The progresses in this area of research have revealed the flexibility of cancer cells that alternate between glycolytic and oxidative metabolism to cope with their conditions of development while sharing their energetic resources.

Toll-like receptor expression and function differ between splenic marginal zone B cell lymphoma and splenic diffuse red pulp B cell lymphoma.

In splenic marginal zone lymphoma (SMZL), specific and functional Toll-like Receptor (TLR) patterns have been recently described, suggesting their involvement in tumoral proliferation. Splenic diffuse red pulp lymphoma with villous lymphocytes (SDRPL) is close to but distinct from SMZL, justifying here the comparison of TLR patterns and functionality in both entities. Distinct TLR profiles were observed in both lymphoma subtypes.

Exome sequencing identifies recurrent alterations and the absence of , and mutations in splenic diffuse red pulp small B-cell lymphoma.

Splenic diffuse red pulp lymphoma is an indolent small B-cell lymphoma recognized as a provisional entity in the World Health Organization 2008 classification. Its precise relationship to other related splenic B-cell lymphomas with frequent leukemic involvement or other lymphoproliferative disorders remains undetermined. We performed whole-exome sequencing to explore the genetic landscape of ten cases of splenic diffuse red pulp lymphoma using paired tumor and normal samples.

Mature IgM-expressing plasma cells sense antigen and develop competence for cytokine production upon antigenic challenge.

Dogma holds that plasma cells, as opposed to B cells, cannot bind antigen because they have switched from expression of membrane-bound immunoglobulins (Ig) that constitute the B-cell receptor (BCR) to production of the secreted form of immunoglobulins. Here we compare the phenotypical and functional attributes of plasma cells generated by the T-cell-dependent and T-cell-independent forms of the hapten NP. We show that the nature of the secreted Ig isotype, rather than the chemical structure of the immunizing antigen, defines two functionally distinct populations of plasma cells.

CD1d-restricted peripheral T cell lymphoma in mice and humans.

Peripheral T cell lymphomas (PTCLs) are a heterogeneous entity of neoplasms with poor prognosis, lack of effective therapies, and a largely unknown pathophysiology. Identifying the mechanism of lymphomagenesis and cell-of-origin from which PTCLs arise is crucial for the development of efficient treatment strategies. In addition to the well-described thymic lymphomas, we found that p53-deficient mice also developed mature PTCLs that did not originate from conventional T cells but from CD1d-restricted NKT cells.

Compromising the unfolded protein response induces autophagy-mediated cell death in multiple myeloma cells.

Objective: To determine whether the Unfolded Protein Response (UPR) sensors (PERK, ATF6 and IRE-1) can be targeted to promote death of Multiple Myeloma (MM) cells.

Methods: We have knocked-down separately each UPR stress sensor in human MM cell lines using RNA interference and followed MM cell death by monitoring the membrane, mitochondrial and nuclear alterations. Involvement of caspases in MM cell death consecutive to UPR sensor knock-down was analyzed by western blotting, measurement of their enzymatic activity using fluorigenic substrates and susceptibility to a pan-caspase inhibitor.