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 hematological cancers, such as T-cell acute lymphoblastic leukemia (T-ALL), whereby PTEN loss defines poor-prognosis patients. We investigated the metabolic rewiring induced by PTEN loss in T-ALL, aiming at identifying novel metabolic vulnerabilities. We showed that the enzyme ATP citrate lyase (ACLY) is strictly required for the transformation of thymic immature progenitors and for the growth of human T-ALL, which remain dependent on ACLY activity even upon transformation.

DNA methylation as a new tool for the differential diagnosis between T-LBL and lymphocyte-rich thymoma.

T-lymphoblastic lymphoma (T-LBL) and thymoma are two rare primary tumors of the thymus deriving either from T-cell precursors or from thymic epithelial cells, respectively. Some thymoma subtypes (AB, B1, and B2) display numerous reactive terminal deoxynucleotidyl transferase-positive (TdT) T-cell precursors masking epithelial tumor cells. Therefore, the differential diagnosis between T-LBL and TdT T-lymphocyte-rich thymoma could be challenging, especially in the case of needle biopsy.

Comprehensive Genetic Profiling Reveals Frequent Alterations of Driver Genes on the X Chromosome in Extranodal NK/T-cell Lymphoma.

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1.

PHF6-altered T-ALL Harbor Epigenetic Repressive Switch at Bivalent Promoters and Respond to 5-Azacitidine and Venetoclax.

Purpose: To assess the impact of PHF6 alterations on clinical outcome and therapeutical actionability in T-cell acute lymphoblastic leukemia (T-ALL).

Experimental Design: We described PHF6 alterations in an adult cohort of T-ALL from the French trial Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 and retrospectively analyzed clinical outcomes between PHF6-altered (PHF6ALT) and wild-type patients. We also used EPIC and chromatin immunoprecipitation sequencing data of patient samples to analyze the epigenetic landscape of PHF6ALT T-ALLs.

From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia.

Cancer cells utilize the main de novo pathway and the alternative salvage pathway for deoxyribonucleotide biosynthesis to achieve adequate nucleotide pools. Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for anti-proliferative therapies for cancers where it is essential. Here, we present the development of a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations.

IL-7 receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK inhibition.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted therapies. Activating mutations of interleukin-7-receptor pathway genes (IL-7Rp) play a proven leukemia-supportive role in T-ALL. JAK inhibitors, such as ruxolitinib, have recently demonstrated preclinical efficacy.

Oncogenetic landscape of T-cell lymphoblastic lymphomas compared to T-cell acute lymphoblastic leukemia.

In the latest 2016 World Health Organization classification of hematological malignancies, T-cell lymphoblastic lymphoma (T-LBL) and lymphoblastic leukemia (T-ALL) are grouped together into one entity called T-cell lymphoblastic leukemia/lymphoma (T-LBLL). However, the question of whether these entities represent one or two diseases remains. Multiple studies on driver alterations in T-ALL have led to a better understanding of the disease while, so far, little data on genetic profiles in T-LBL is available.

PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is a group of aggressive hematological cancers with dismal outcomes that are in need of new therapeutic options. Polycomb repressor complex 2 (PRC2) loss-of-function alterations were reported in pediatric T-ALL, yet their clinical relevance and functional consequences remain elusive. Here, we extensively analyzed PRC2 alterations in a large series of 218 adult T-ALL patients.

Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup.

Adult "T cell" acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is associated with poor outcomes, requiring additional therapeutic options. The DNA methylation landscapes of adult T-ALL remain undercharacterized. Here, we systematically analyzed the DNA methylation profiles of normal thymic-sorted T cell subpopulations and 143 primary adult T-ALLs as part of the French GRAALL 2003-2005 trial.

Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL.

IDH1 and IDH2 mutations (IDH1/2) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2 inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2.

Adenylate kinase 2 expression and addiction in T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) represents the malignant expansion of immature T cells blocked in their differentiation. T-ALL is still associated with a poor prognosis, mainly related to occurrence of relapse or refractory disease. A critical medical need therefore exists for new therapies to improve the disease prognosis.

Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation.

Cell differentiation is accompanied by epigenetic changes leading to precise lineage definition and cell identity. Here we present a comprehensive resource of epigenomic data of human T cell precursors along with an integrative analysis of other hematopoietic populations. Although T cell commitment is accompanied by large scale epigenetic changes, we observed that the majority of distal regulatory elements are constitutively unmethylated throughout T cell differentiation, irrespective of their activation status.

BET protein targeting suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer and elicits anti-tumor immune response.

Therapeutic strategies aiming to leverage anti-tumor immunity are being intensively investigated as they show promising results in cancer therapy. The PD-1/PD-L1 pathway constitutes an important target to restore functional anti-tumor immune response. Here, we report that BET protein inhibition suppresses PD-1/PD-L1 in triple-negative breast cancer.

BRD4 Regulates Metastatic Potential of Castration-Resistant Prostate Cancer through AHNAK.

The inevitable progression of advanced prostate cancer to castration resistance, and ultimately to lethal metastatic disease, depends on primary or acquired resistance to conventional androgen deprivation therapy (ADT) and accumulated resistance strategies to evade androgen receptor (AR) suppression. In prostate cancer cells, AR adaptations that arise in response to ADT are not singular, but diverse, and include gene amplification, mutation, and even complete loss of receptor expression. Collectively, each of these AR adaptations contributes to a complex, heterogeneous, ADT-resistant tumor.

Inflammatory signatures distinguish metabolic health in African American women with obesity.

Obesity-driven Type 2 diabetes (T2D) is a systemic inflammatory condition associated with cardiovascular disease. However, plasma cytokines and tissue inflammation that discriminate T2D risk in African American women with obese phenotypes are not well understood. We analyzed 64 circulating cytokines and chemokines in plasma of 120 African American women enrolled in the Black Women's Health Study.

BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment.

Obesity and its associated pathology Type 2 diabetes are two chronic metabolic and inflammatory diseases that promote breast cancer progression, metastasis, and poor outcomes. Emerging critical opinion considers unresolved inflammation and abnormal metabolism separately from obesity; settings where they do not co-occur can inform disease mechanism. In breast cancer, the tumor microenvironment is often infiltrated with T effector and T regulatory cells programmed by metabolic signaling.