Since the publication of the 2020 World Health Organization classification of soft tissue and bone tumors, the classification of "fibroblastic" tumors has expanded to include a novel subset of tumors characterized by PRRX1::NCOA1/2 gene fusions. These tumors defy conventional classification and are morphologically distinct, characterized by a multi-nodular growth of bland spindle cells suspended in a myxo-collagenous stroma with mild cytologic atypia, "staghorn-like" vessels, and variable perivascular hyalinization. Mitotic activity is rare, and necrosis is not identified. Herein, we present six additional cases of PRRX1-rearranged mesenchymal tumors, including five cases with PRRX1::NCOA1 fusion and one case with PRRX1::KMT2D fusion. Three cases (3/6, 50%) demonstrated focal co-expression of S100 protein and SOX10, thereby expanding the immunohistochemical profile of this emerging entity. Like prior reported cases, there was no evidence of malignant behavior on short-term follow-up. The novel fusion, PRRX1::KMT2D, further expands the molecular spectrum of this entity and leads to a proposed revision of the provisional nomenclature to "PRRX1-rearranged mesenchymal tumor" to both accommodate non-NCOA1/2 fusion partners and allow for the possibility of partial neural or neuroectodermal differentiation.

• Klíčová slova
• KMT2D, Mesenchymal tumor, NCOA1, PRRX1, Soft tissue, Spindle cell,
• MeSH
• fúze genů MeSH
• homeodoménové proteiny genetika   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory kostí * MeSH
• nádory měkkých tkání * genetika   patologie   MeSH
• nádory z pojivové a měkké tkáně * MeSH
• proteiny S100 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• homeodoménové proteiny MeSH
• nádorové biomarkery MeSH
• proteiny S100 MeSH
• PRRX1 protein, human MeSH Prohlížeč

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

• MeSH
• akutní lymfatická leukemie * genetika   MeSH
• akutní myeloidní leukemie * genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• histonlysin-N-methyltransferasa * genetika   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• protoonkogenní protein MLL * genetika   MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• histonlysin-N-methyltransferasa * MeSH
• KMT2A protein, human MeSH Prohlížeč
• protoonkogenní protein MLL * MeSH

PURPOSE: We aimed to study prognostic factors and efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in first remission of patients with noninfant childhood acute lymphoblastic leukemia (ALL) with 11q23/KMT2A rearrangements treated with chemotherapy regimens between 1995 and 2010. PATIENTS AND METHODS: Data were retrospectively retrieved from 629 patients with 11q23/KMT2A-rearranged ALL from 17 members of the Ponte-di-Legno Childhood ALL Working Group. Clinical and biologic characteristics, early response assessed by minimal residual disease at the end of induction (EOI) therapy, and allo-HSCT were analyzed for their impact on outcomes. RESULTS: A specific 11q23/KMT2A translocation partner gene was identified in 84.3% of patients, with the most frequent translocations being t(4;11)(q21;q23) (n = 273; 51.5%), t(11;19)(q23;p13.3) (n = 106; 20.0%), t(9;11)(p21_22;q23) (n = 76; 14.3%), t(6;11)(q27;q23) (n = 20; 3.8%), and t(10;11)(p12;q23) (n = 14; 2.6%); 41 patients (7.7%) had less frequently identified translocation partner genes. Patient characteristics and early response varied among subgroups, indicating large biologic heterogeneity and diversity in therapy sensitivity among 11q23/KMT2A-rearranged ALL. The EOI remission rate was 93.2%, and the 5-year event-free survival (EFS) for the entire cohort was 69.1% ± 1.9%, with a range from 41.7% ± 17.3% for patients with t(9;11)-positive T-ALL (n = 9) and 64.8% ± 3.0% for patients with t(4;11)-positive B-ALL (n = 266) to 91.2% ± 4.9% for patients with t(11;19)-positive T-ALL (n = 34). Low EOI minimal residual disease was associated with favorable EFS, and induction failure was particularly predictive of nonresponse to further therapy and relapse and poor EFS. In addition, EFS was not improved by allo-HSCT compared with chemotherapy only in patients with both t(4;11)-positive B-ALL (n = 64 v 51; P = .10) and 11q23/KMT2A-rearranged T-ALL (n = 16 v 10; P = .69). CONCLUSION: Compared with historical data, prognosis of patients with noninfant 11q23/KMT2A-rearranged ALL has improved, but allo-HSCT failed to affect outcome. Targeted therapies are needed to reduce relapse and treatment-related mortality rates.

• MeSH
• akutní lymfatická leukemie * terapie   MeSH
• biologické přípravky * MeSH
• lidé MeSH
• lidské chromozomy, pár 11 MeSH
• lymfoblastická leukemie-lymfom z prekurzorových T-buněk * MeSH
• prognóza MeSH
• recidiva MeSH
• retrospektivní studie MeSH
• reziduální nádor genetika   MeSH
• translokace genetická MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• biologické přípravky * MeSH
• KMT2A protein, human MeSH Prohlížeč

Fetal and adult hematopoietic stem and progenitor cells (HSPCs) are characterized by distinct redox homeostasis that may influence their differential cellular behavior in normal and malignant hematopoiesis. In this work, we have applied a quantitative mass spectrometry-based redox proteomic approach to comprehensively describe reversible cysteine modifications in primary mouse fetal and adult HSPCs. We defined the redox state of 4,438 cysteines in fetal and adult HSPCs and demonstrated a higher susceptibility to oxidation of protein thiols in fetal HSPCs. Our data identified ontogenic changes to oxidation state of thiols in proteins with a pronounced role in metabolism and protein homeostasis. Additional redox proteomic analysis identified oxidation changes to thiols acting in mitochondrial respiration as well as protein homeostasis to be triggered during onset of MLL-ENL leukemogenesis in fetal HSPCs. Our data has demonstrated that redox signaling contributes to the regulation of fundamental processes of developmental hematopoiesis and has pinpointed potential targetable redox-sensitive proteins in in utero-initiated MLL-rearranged leukemia.

• Klíčová slova
• Cysteine oxidative modifications, Developmental biology, Hematopoiesis, Leukemia, Protein translation, Redox proteomics,
• MeSH
• cystein metabolismus   MeSH
• hematopoéza MeSH
• myši MeSH
• oxidace-redukce MeSH
• proteom * metabolismus   MeSH
• proteomika * MeSH
• sulfhydrylové sloučeniny MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cystein MeSH
• proteom * MeSH
• sulfhydrylové sloučeniny MeSH

• MeSH
• histonlysin-N-methyltransferasa genetika   MeSH
• leukemie * MeSH
• lidé MeSH
• protoonkogenní protein MLL * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• histonlysin-N-methyltransferasa MeSH
• protoonkogenní protein MLL * MeSH

• MeSH
• histonlysin-N-methyltransferasa genetika   MeSH
• kohortové studie MeSH
• leukemie genetika   MeSH
• lidé MeSH
• protoonkogenní protein MLL genetika   MeSH
• rekombinantní fúzní proteiny genetika   MeSH
• thiolesterasa ubikvitinu genetika   MeSH
• translokace genetická genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• histonlysin-N-methyltransferasa MeSH
• KMT2A protein, human MeSH Prohlížeč
• protoonkogenní protein MLL MeSH
• rekombinantní fúzní proteiny MeSH
• thiolesterasa ubikvitinu MeSH
• USP2 protein, human MeSH Prohlížeč