LEF1 Intragenic Deletion Induces a Dominant-Negative isoform and unveils a Wnt/β3-Catenin Vulnerability in T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) represents a group of aggressive hematological malignancies characterized by unfavorable prognosis, urging the need for innovative therapeutic strategies. LEF1 is a member of the lymphoid enhancer factor/T-cell factor (LEF/TCF) family of DNA-binding transcription factors, known for their interaction with nuclear β-catenin in the context of the Wnt signaling pathway. Although LEF1's implication in colon cancer is well-documented, its clinical relevance and functional consequences remain elusive in T-ALL.

Towards methylation-based redefinition of TAL1 positive T-cell acute lymphoblastic leukaemia (T-ALL).

TAL1 is one of the most frequently dysregulated oncogenes in T-cell Acute Lymphoblastic Leukaemia (T-ALL). However, the precise frequency and prognostic impact associated with its dysregulation remains unclear and is confounded by TAL1's diverse dysregulation mechanisms. TAL1 dysregulation is detected by TAL1 transcript quantification, though this technique may be subject to interference by TAL1 transcripts deriving from residual haematological cells that physiologically express high levels of the gene.

gain-of-function mutation in Schwann cells leads to severe neuropathy and aerobic glycolysis through a non-cell autonomous effect.

-related disorders are rare genetic disorders due to somatic gain-of-function mutations in during embryonic development, a pathway involved in cell growth, proliferation, and metabolism. Accumulating evidence from patients with -related disorders indicates that peripheral nerves are frequently affected, leading to severe neurological symptoms. However, the exact underlying mechanism of these disorders remains unclear.

First report of successful pregnancies after treatment with alpelisib for PIK3CA-related overgrowth spectrum.

Alpelisib is a selective PI3Kα inhibitor approved for treating PIK3CA-related overgrowth spectrum (PROS), a group of rare malformation disorders. Given that PI3Kα is a ubiquitous protein involved in cell proliferation, understanding the long-term impact of alpelisib on fertility is of critical importance. Here, we report the favorable outcomes of three pregnancies in PROS patients after prolonged treatment with alpelisib.

Oncogenomic profiling in infant-toddler T-ALL identifies NKX2 family genes as drivers linked to favorable outcomes.

T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive hematological malignancy primarily affecting adolescents and young adults and is scarce in infants and toddlers under age 3. Unlike B-ALL, T-ALL in this young population remains poorly characterized due to limited data and lacks evidence-based guidelines to help clinicians determine the optimal treatment approach. In this study, we conducted a comprehensive genetic analysis of infant/toddler T-ALL cases from a French national cohort, utilizing high-throughput targeted sequencing, optical genome mapping, and RNA sequencing.

Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition.

Mutations in PIK3R1 have recently been identified in patients with overgrowth syndromes and complex vascular malformations. PIK3R1 encodes p85α which acts as the regulatory subunit of the lipid kinase PI3Kα. PIK3R1 mutations result in the excessive activation of the AKT/mTOR pathway.

Severe inflammation and lineage skewing are associated with poor engraftment of engineered hematopoietic stem cells in patients with sickle cell disease.

In sickle cell disease (SCD), the β6 substitution in the β-globin leads to red blood cell sickling. The transplantation of autologous, genetically modified hematopoietic stem and progenitor cells (HSPCs) is a promising treatment option for patients with SCD. We completed a Phase I/II open-label clinical trial (NCT03964792) for patients with SCD using a lentiviral vector (DREPAGLOBE) expressing a potent anti-sickling β-globin.

Surface pTα expression predicts LCK activation and preclinical synergy of LCK and JAK coinhibition in adult T-ALL.

Refractory and/or relapsing T-cell acute lymphoblastic leukemia (T-ALL) remains a major therapeutic challenge. The pre-T-cell receptor (TCR) pathway has recently emerged as a therapeutic target via LCK inhibition in this context. However, there is a need for simple and quickly assessable biomarkers to predict sensitivity to LCK inhibitors.

TLE4 is a repressor of the oncogenic activity of TLX3 in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease originating from the malignant transformation of T-cell progenitors, caused by the accumulation of genetic aberrations. One-fifth of T-ALL patients are characterized by ectopic expression of the homeobox transcription factor TLX3. However, the role of TLX3 in T-ALL remains elusive, partly due to the lack of suitable study models.

Neo-enhancers in T-cell acute lymphoblastic Leukaemia (T-ALL) and beyond.

T-cell acute lymphoblastic leukaemia (T-ALL) is a rare aggressive haematological malignancy characterised by the clonal expansion of immature T-cell precursors. It accounts for 15% of paediatric and 25% of adult ALL. T-ALL is associated with the overexpression of major transcription factors (TLX1/3, TAL1, HOXA) that drive specific transcriptional programmes and constitute the molecular classifying subgroups of T-ALL.

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.

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.

Chloride deregulation and GABA depolarization in MTOR-related malformations of cortical development.

Focal cortical dysplasia, hemimegalencephaly and cortical tubers are paediatric epileptogenic malformations of cortical development (MCDs) frequently pharmacoresistant and mostly treated surgically by the resection of epileptic cortex. Availability of cortical resection samples has allowed significant mechanistic discoveries directly from human material. Causal brain somatic or germline mutations in the AKT/PI3K/DEPDC5/MTOR genes have been identified.

Sotorasib for Vascular Malformations Associated with G12C Mutation.

gain-of-function mutations are frequently observed in sporadic arteriovenous malformations. The mechanisms underlying the progression of such -driven malformations are still incompletely understood, and no treatments for the condition are approved. Here, we show the effectiveness of sotorasib, a specific KRAS G12C inhibitor, in reducing the volume of vascular malformations and improving survival in two mouse models carrying a mosaic G12C mutation.

Dependence on mitochondrial respiration of malignant T cells reveals a new therapeutic target for angioimmunoblastic T-cell lymphoma.

Cancer metabolic reprogramming has been recognized as one of the cancer hallmarks that promote cell proliferation, survival, as well as therapeutic resistance. Up-to-date regulation of metabolism in T-cell lymphoma is poorly understood. In particular, for human angioimmunoblastic T-cell lymphoma (AITL) the metabolic profile is not known.

Targeted therapy for capillary-venous malformations.

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations.

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.