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The reintegration of excised signal joints resulting from human V(D)J recombination was described as a potent source of genomic instability in human lymphoid cancers. However, such molecular events have not been recurrently reported in clinical patient lymphoma/leukemia samples. Using a specifically designed NGS-capture pipeline, we here demonstrated the reintegration of T-cell receptor excision circles (TRECs) in 20/1533 (1.3%) patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). Remarkably, the reintegration of TREC recurrently targeted the tumor suppressor gene, ZFP36L2, in 17/20 samples. Thus, our data identified a new and hardly detectable mechanism of gene deregulation in lymphoid cancers providing new insights in human oncogenesis.

Background Anaplastic large cell lymphoma positive for ALK (ALK+ ALCL) is a rare type of non-Hodgkin lymphoma. This lymphoma is caused by chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK). In this study, we aimed to identify mechanisms of transformation and therapeutic targets by generating a model of ALK+ ALCL lymphomagenesis ab initio with the specific NPM-ALK fusion. Methods We performed CRISPR/Cas9-mediated genome editing of the NPM-ALK chromosomal translocation in primary human activated T lymphocytes. Results Both CD4+ and CD8+ NPM-ALK-edited T lymphocytes showed rapid and reproducible competitive advantage in culture and led to in vivo disease development with nodal and extra-nodal features. Murine tumors displayed the phenotypic diversity observed in ALK+ ALCL patients, including CD4+ and CD8+ lymphomas. Assessment of transcriptome data from models and patients revealed global activation of the WNT signaling pathway, including both canonical and non-canonical pathways, during ALK+ ALCL lymphomagenesis. Specifically, we found that the WNT signaling cell surface receptor ROR2 represented a robust and genuine marker of all ALK+ ALCL patient tumor samples. Conclusions In this study, ab initio modeling of the ALK+ ALCL chromosomal translocation in mature T lymphocytes enabled the identification of new therapeutic targets. As ROR2 targeting approaches for other cancers are under development (including lung and ovarian tumors), our findings suggest that ALK+ ALCL cases with resistance to current therapies may also benefit from ROR2 targeting strategies.

Several obstacles to the production, expansion and genetic modification of immunotherapeutic T cells in vitro have restricted the widespread use of T-cell immunotherapy. In the context of HSCT, delayed naïve T-cell recovery contributes to poor outcomes. A novel approach to overcome the major limitations of both T-cell immunotherapy and HSCT would be to transplant human T-lymphoid progenitors (HTLPs), allowing reconstitution of a fully functional naïve T-cell pool in the patient thymus. However, it is challenging to produce HTLPs in the high numbers required to meet clinical needs. Here, we found that adding tumor necrosis factor alpha (TNFα) to a DL-4-based culture system led to the generation of a large number of nonmodified or genetically modified HTLPs possessing highly efficient in vitro and in vivo T-cell potential from either CB HSPCs or mPB HSPCs through accelerated T-cell differentiation and enhanced HTLP cell cycling and survival. This study provides a clinically suitable cell culture platform to generate high numbers of clinically potent nonmodified or genetically modified HTLPs for accelerating immune recovery after HSCT and for T-cell-based immunotherapy (including CAR T-cell therapy).

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. Genetic analysis revealed the absence of TLX1/3 dysregulation. Instead, we identified a significant prevalence of NKX2 rearrangements (n = 9, 33%), co‐occurring with MYB alterations (n = 5/9) or chromothripsis‐like events (n = 3/9). Additional findings included TAL1/‐like anomalies (30%), STAG2::LMO2 (15%), ETS rearrangements (15%), and rarely, KMT2A rearrangements (7%). Comparative analyses with 245 patients aged 3–18 years, enrolled in the pediatric FRALLE2000T French protocol, underscored the distinct clinical and genetic profiles of infants/toddlers. Despite presenting with higher rates of hyperleukocytosis and slower responses to treatment, they demonstrated comparable survival outcomes to older pediatric patients, with a 5‐year overall survival (OS) rate of 75.4% (95% confidence interval [CI]: 60.0%–94.8%) versus 75.2% (95% CI: 69.8%–81.1%), p = 0.86. Notably, alterations in NKX2, KMT2A, and STAG2::LMO2 delineated oncogenic subgroups exhibiting a remarkable 100% OS rate, while patients with TAL1 or ETS dysregulation experienced less favorable outcomes. This was further supported by analyses of data from the COG AALL0434 trial, enhancing our understanding of T‐ALL in infants/toddlers. Large‐scale collaborative studies remain essential to confirm these findings and refine treatment strategies.

Anaplastic large cell lymphoma (ALCL) is a mature T cell neoplasm that often expresses the CD4+ T cell surface marker. It usually harbors the t(2;5) (p23;q35) translocation, leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. We demonstrated that in vitro transduction of normal human CD4+ T lymphocytes with NPM-ALK results in their immortalization and malignant transformation. The tumor cells displayed morphological and immunophenotypical characteristics of primary patient-derived anaplastic large cell lymphomas. Cell growth, proliferation, and survival were strictly dependent on NPM-ALK activity and include activation of the key factors STAT3 and DNMT1 and expression of CD30 (the hallmark of anaplastic large-cell lymphoma). Implantation of NPM-ALK-transformed CD4+ T lymphocytes into immunodeficient mice resulted in the formation of tumors indistinguishable from patients' anaplastic large cell lymphomas. Integration of \"Omic\" data revealed that NPM-ALK-transformed CD4+ T lymphocytes and primary NPM-ALK+ ALCL biopsies share similarities with early T cell precursors. Of note, these NPM-ALK+ lymphoma cells overexpress stem cell regulators (OCT4, SOX2, and NANOG) and HIF2A, which is known to affect hematopoietic precursor differentiation and NPM-ALK+ cell growth. Altogether, for the first time our findings suggest that NPM-ALK could restore progenitor-like features in mature CD30+ peripheral CD4+ T cells, in keeping with a thymic progenitor-like pattern.

The T‐cell Leukemia Homeobox 1 (TLX1) oncogene is frequently deregulated in T‐cell acute lymphoblastic leukemia (T‐ALL) and T‐cell lymphoblastic lymphoma (T‐LBL). In most instances, TLX1 overexpression results from its juxtaposition with a T‐cell receptor (TCR) locus caused by interchromosomal translocations. However, in the subset of non‐TCR‐translocated TLX1‐positive (non‐TCR TLX1+) T‐ALL cases, the underlying mechanisms driving TLX1 overexpression and their clinico‐biological implications remain unclear. By integrating high‐resolution data from next‐generation sequencing, fluorescence in situ hybridization, karyotyping, optical genome mapping, and long‐read whole‐genome sequencing across a cohort of 1122 adult and pediatric T‐ALL/T‐LBL cases, we identified TLX1 overexpression in 11% of T‐ALL/T‐LBL cases, with an unexpected 14% incidence of non‐TCR TLX1+ cases among TLX1+ cases. Non‐TCR TLX1 + T‐ALL cases show distinct clinico‐biological features, including a lower frequency of cortical phenotype compared to the TCR‐translocated TLX1+ (TCR TLX1+) subgroup, regardless of TLX1 expression levels. In non‐TCR TLX1⁺ cases, TLX1 deregulation results mostly (83%) from the hijacking of the ANKRD1 and PCGF5 enhancer at 10q23.31 through various chromosomal aberrations. Genomic analyses revealed that these aberrations juxtapose the ANKRD1 and PCGF5 enhancer with TLX1, driving its overexpression. Importantly, survival analysis revealed that non‐TCR TLX1+ patients had significantly poorer outcomes compared to their TCR TLX1⁺ counterparts (3y‐OS: 55% vs. 90%, P < 0.001 and 3y‐DFS: 45% vs. 75%, P = 0.02). These findings, consistent with our previous observations in TAL1‐driven T‐ALL, confirm that the clinico‐biological impact of an oncogene is influenced by the specific mechanism underlying its deregulation.

T-cell receptor gene beta (TCRβ) gene rearrangement represents a complex, tightly regulated molecular mechanism involving excision, deletion and recombination of DNA during T-cell development. RUNX1, a well-known transcription factor for T-cell differentiation, has recently been described to act in addition as a recombinase cofactor for TCRδ gene rearrangements. In this work we employed a RUNX1 knock-out mouse model and demonstrate by deep TCRβ sequencing, immunostaining and chromatin immunoprecipitation that RUNX1 binds to the initiation site of TCRβ rearrangement and its homozygous inactivation induces severe structural changes of the rearranged TCRβ gene, whereas heterozygous inactivation has almost no impact. To compare the mouse model results to the situation in Acute Lymphoblastic Leukemia (ALL) we analyzed TCRβ gene rearrangements in T-ALL samples harboring heterozygous Runx1 mutations. Comparable to the Runx1 +/− mouse model, heterozygous Runx1 mutations in T-ALL patients displayed no detectable impact on TCRβ rearrangements. Furthermore, we reanalyzed published sequence data from recurrent deletion borders of ALL patients carrying an ETV6-RUNX1 translocation. RUNX1 motifs were significantly overrepresented at the deletion ends arguing for a role of RUNX1 in the deletion mechanism. Collectively, our data imply a role of RUNX1 as recombinase cofactor for both physiological and aberrant deletions.

Ovarian cancer is the leading cause of mortality in women with gynaecological cancers. Cytoreductive surgery has been considered as a mainstay in manage­ment of ovarian cancer for a long time. Further chemotherapy, based on platinum compounds and taxanes given in an adjuvant setting, allows 5-year survival to be achieved in 10-30% of ovarian cancer patients. Among these cases, it is thought that 5-10% of patients have familial or hereditary disease in which mutations within BRCA genes are the main culprits of 80-90% of ovarian cancer sufferers. The risk of ovarian cancer development in carriers of a mutated BRCA1 gene is 16-60%, which underlines the great need for a precise tool in the form of molecular tests. Now it is time for development of a direct-to-consumer (DTC) strategy that offers commercially available molecular tests with wide utility.

Renal cell carcinoma is highly resistant to systemic chemotherapy - the objective response rates do not exceed several percent for as well single agents as combine regimens. The existence of multifactorial multidrug resistance in this carcinoma is the reason of this state. Many cytostatics are chased away from renal cancer cells by the efflux pumps - MDR and MRP transporters. They are plasma membrane proteins, using energy from ATP hydrolysis to remove outside the cells such drugs like Vinca alkaloids, actinomycin-D, taxanes and cisplatin. Detoxification processes, using cytochrome P40s and glutathione, are strongly involved in resistance to ifosphamide, paclitaxel and cisplatin, carboplatin, doxorubicin, respectively. The levels of topoisomerase IIα - the enzyme involved in controlling the topologic states of DNA - are decreased in renal cell carcinoma lines with acquired resistance to etoposide. The relationship between drug resistance and expression of some oncogenes, like erbB-1, erbB-2, c-fos and Bcl-2 was also found. Mechanisms of multidrug resistance, involving both MDR and MRP transporters and glutathione, are very often the intrinsic ability of neoplastic cells, due to their existence in normal cells. Especially, this situation takes place in carcinomas of organs with excretory function. Renal cancer is considered to develop from proximal tubular epithelial cells, in which xenobiotics exporting pathways work very effectively. After tumor originating these mechanisms became the natural base of multidrug resistance developing. These circumstances seem to be the main reason of high resistance of renal cancer to a broad drug spectrum, commonly used in contemporary therapy.