AIMS: This study aimed to examine changes in the repertoire of functional T-cells specific for six leukemia-associated antigens (LAA), including WT1, PRAME, MUC1, CCNA1, NPM1, and NPM1c, during immune reconstitution following allogeneic transplantation of hematopoietic stem cells (HSCT) in patients with acute myeloid leukemia. PATIENTS & METHODS: LAA-specific T cell response was measured by ELISPOT- IFNγ and intracellular cytokine staining in 47 patients before starting conditioning therapy (baseline) and 7 months after HSCT. RESULTS: The positive cumulative LAA-specific T cell response before HSCT was associated with a decreased risk of relapse after HSCT. The prevalent genetic aberration - an internal tandem duplication of Fms 3 - related receptor tyrosine kinase, which has been previously implicated in immune escape mechanisms, is presented here for the first time as a factor associated with the absence of an adaptive T cell response against multiple LAAs. T-cell specific responses against wild-type and mutated NPM1 antigens were less frequent in the study cohort and did not correlate with mutations in the NPM1 gene. CONCLUSIONS: Our results showed that the T-cell response to LAA can be reconstituted after HSCT. Measurement of functional pre-transplant T-cell responses against multiple LAAs could help to find patients with an increased risk of relapse.

• MeSH
• akutní myeloidní leukemie * terapie   imunologie   genetika   MeSH
• antigeny nádorové imunologie   MeSH
• dospělí MeSH
• homologní transplantace MeSH
• jaderné proteiny genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mucin 1 genetika   imunologie   MeSH
• mutace * MeSH
• nukleofosmin * MeSH
• proteiny WT1 imunologie   genetika   MeSH
• recidiva MeSH
• senioři MeSH
• T-lymfocyty * imunologie   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• tyrosinkinasa 3 podobná fms * genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Despite extensive research, the molecular role of AGR2 in the progression and metastasis of colorectal cancer (CRC) has not been fully characterized. We used quantitative mass spectrometry (SWATH MS) to identify differentially expressed proteins in paired CRC cell models of the SW480 and SW620 cell lines in response to AGR2 protein level manipulation. Relying on the results from SWATH MS and subsequent immunochemical validation, we selected NMP3 as the top candidate protein associated with AGR2 in CRC tumour cells in our screen. RT‒qPCR and immunochemical analysis confirmed the involvement of AGR2-mediated regulation of NPM3 at the transcriptional and posttranscriptional levels. Since PD-L1 is a constituent of the NPM3 regulatory axis, we aimed to correlate the changes in PD-L1 to the differential expression of AGR2 in our cell models. We found that AGR2 positively regulates PD-L1 levels in both SW480 and SW620 cell lines; additionally, several different CRC patient transcriptome cohorts confirmed the association of AGR2 with PD-L1. Our work reveals a new AGR2-NPM3 regulatory axis and the involvement of AGR2 in the regulation of PD-L1, which paves the way for the association of AGR2 with immune evasion in CRC cells.

• MeSH
• antigeny CD274 * metabolismus   genetika   MeSH
• jaderné proteiny metabolismus   genetika   MeSH
• kolorektální nádory * genetika   metabolismus   patologie   MeSH
• lidé MeSH
• mukoproteiny * metabolismus   genetika   MeSH
• nádorové buněčné linie MeSH
• nukleofosmin * MeSH
• onkogenní proteiny * metabolismus   genetika   MeSH
• proteiny * metabolismus   genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

We assessed outcomes of allogeneic transplantation (HSCT) in favorable risk AML in CR1 over 3 time periods. 1850 patients were included, 2005 to 2009- 222, 2010 to 2014 -392, and 2015 to 2021-1236; 526 with t (8:21), 625 with inv (16), and 699 with NPM1mutFLT3WT. Patients transplanted in 2015-2021 were older (p < 0.0001) with more patients ≥60 years of age (p < 0.0001). The most frequent diagnosis in 2015-2021 was NPM1mutFLT3WT vs. t (8:21) in the 2 earlier periods, (p < 0001). Haploidentical transplants (Haplo) increased from 5.9% to 14.5% (p < 0.0001). Graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) was more frequent in 2015-2021 vs. the other 2 periods (p < 0.0001). On multivariate analysis, incidence of total chronic GVHD was reduced in HSCTs performed ≥2015 vs. those performed in 2005-2009, hazard ratio (HR) = 0.74 (95% CI 0.56-0.99, p = 0.046) and GVHD-free, relapse-free survival (GRFS) improved for patients transplanted from 2010-2014 vs. those transplanted in 2005-2009, HR = 0.74 (95% CI 0.56-0.98, p = 0.037). Other HSCT outcomes did not differ with no improvement ≥2015. LFS, OS, and GRFS were inferior in patients with t (8:21) with HR = 1.32 (95% CI 1.03-1.68, p = 0.026), HR = 1.38 (95% CI 1.04-1.83, p = 0.027) and HR = 01.25 (95% CI 1.02-1.53, p = 0.035), respectively. In conclusion, this retrospective analysis of HSCT in patients with favorable risk AML, transplanted over 16 years showed an increased number of transplants in patients ≥60 years, from Haplo donors with PTCy. Most importantly, 3-year GRFS improved ≥2010 and total chronic GVHD reduced ≥2015, with no significant change in other HSCT outcomes.

• MeSH
• akutní myeloidní leukemie * terapie   MeSH
• alografty MeSH
• dospělí MeSH
• homologní transplantace metody   MeSH
• indukce remise MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoc štěpu proti hostiteli prevence a kontrola   etiologie   MeSH
• nukleofosmin MeSH
• retrospektivní studie MeSH
• senioři MeSH
• transplantace hematopoetických kmenových buněk * metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

• MeSH
• akutní myeloidní leukemie * genetika   vrozené   MeSH
• genetické testování MeSH
• isocitrátdehydrogenasa genetika   MeSH
• lidé MeSH
• mutace * MeSH
• nukleofosmin genetika   MeSH
• prognóza MeSH
• statistika jako téma MeSH
• tyrosinkinasa 3 podobná fms genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Frequency, distribution and prognostic meaning of ALK-partner genes other than NPM1 in ALK-positive anaplastic large-cell lymphoma (ALCL) are unknown. Forty-nine of 316 ALCL diagnosed in the NHL-BFM study group showed no nuclear ALK expression suggestive of a variant ALK-partner; 41 were analysed by genomic capture high-throughput sequencing or specific RT-PCRs. NPM1::ALK was detected in 13 cases. Among the 28 patients with a non-NPM1::ALK-fusion partner, ATIC (n = 8; 29%) and TPM3 (n = 9; 32%) were the most common. Five of eight patients with ATIC::ALK-positive ALCL relapsed, none of nine with TPM3::ALK. Variant ALK-partners are rare and potentially associated with different prognoses.

• MeSH
• anaplastická lymfomová kináza * genetika   analýza   MeSH
• anaplastický velkobuněčný lymfom * genetika   patologie   MeSH
• dítě MeSH
• fúzní onkogenní proteiny genetika   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• nukleofosmin * MeSH
• předškolní dítě MeSH
• prognóza MeSH
• tropomyosin MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Genetic lesions of IKZF1 are frequent events and well-established markers of adverse risk in acute lymphoblastic leukemia. However, their function in the pathophysiology and impact on patient outcome in acute myeloid leukemia (AML) remains elusive. In a multicenter cohort of 1606 newly diagnosed and intensively treated adult AML patients, we found IKZF1 alterations in 45 cases with a mutational hotspot at N159S. AML with mutated IKZF1 was associated with alterations in RUNX1, GATA2, KRAS, KIT, SF3B1, and ETV6, while alterations of NPM1, TET2, FLT3-ITD, and normal karyotypes were less frequent. The clinical phenotype of IKZF1-mutated AML was dominated by anemia and thrombocytopenia. In both univariable and multivariable analyses adjusting for age, de novo and secondary AML, and ELN2022 risk categories, we found mutated IKZF1 to be an independent marker of adverse risk regarding complete remission rate, event-free, relapse-free, and overall survival. The deleterious effects of mutated IKZF1 also prevailed in patients who underwent allogeneic hematopoietic stem cell transplantation (n = 519) in both univariable and multivariable models. These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling.

• MeSH
• akutní myeloidní leukemie * patologie   MeSH
• dospělí MeSH
• lidé MeSH
• mutace MeSH
• nukleofosmin MeSH
• prognóza MeSH
• transkripční faktor Ikaros genetika   MeSH
• transkripční faktory genetika   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• tyrosinkinasa 3 podobná fms genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

• MeSH
• akutní myeloidní leukemie * genetika   MeSH
• kostní dřeň MeSH
• lidé MeSH
• mutace MeSH
• nukleofosmin * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH

Specific C-terminal nucleophosmin (NPM) mutations are related to the acute myeloid leukaemia and cause mistargeting of mutated NPM (NPMmut) to the cytoplasm. Consequently, multiple NPM-interacting partners, e.g., the tumour suppressor p53, become also mislocalized. We found that ubiquitin ligase Mdm2 mislocalizes to the cytoplasm in the presence of NPMmut as well. Since p53 interacts with Mdm2, we searched for the NPMmut-p53-Mdm2 complex and interactions of its constituents in live cells and cell lysates using fluorescently tagged proteins, fluorescence lifetime imaging and immunoprecipitation. We proved existence of the ternary complex, which likely adopts a chain-like configuration. Interaction between Mdm2 and NPMmut was not detected, even under conditions of upregulated Mdm2 and p53 induced by Actinomycin D. We assume that p53 serves in the complex as a bridging link between Mdm2 and NPMmut. This conclusion was supported by disruption of the Mdm2-p53 interaction by Nutlin-3A, which resulted in relocalization of Mdm2 to the nucleus, while both NPMmut and p53 remained in the cytoplasm. Importantly, silencing of p53 also prevented mislocalization of Mdm2 in the presence of NPMmut.

• MeSH
• cytoplazma genetika   metabolismus   MeSH
• jaderné proteiny * genetika   metabolismus   MeSH
• mutace MeSH
• nádorový supresorový protein p53 * genetika   metabolismus   MeSH
• nukleofosmin MeSH
• protoonkogenní proteiny c-mdm2 genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• mutace NPM1, inhibitory meninu,
• MeSH
• akutní myeloidní leukemie * diagnóza   farmakoterapie   genetika   patofyziologie   MeSH
• farmakoterapie klasifikace   MeSH
• imunohistochemie MeSH
• imunoterapie adoptivní metody   MeSH
• lidé MeSH
• mutace * MeSH
• nukleofosmin genetika   škodlivé účinky   MeSH
• prognóza MeSH
• protein exportin 1 antagonisté a inhibitory   MeSH
• protinádorové látky terapeutické užití   MeSH
• reziduální nádor MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

• Klíčová slova
• mutace NPM1,
• MeSH
• akutní myeloidní leukemie * diagnóza   genetika   MeSH
• imunohistochemie MeSH
• lidé MeSH
• mutace * MeSH
• myelodysplastické syndromy diagnóza   genetika   MeSH
• nukleofosmin genetika   škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH