Targeting the surface of malignant cells has evolved into a cornerstone in cancer therapy, paradigmatically introduced by the success of humoral immunotherapy against CD20 in malignant lymphoma. ...However, tumor cell susceptibility to immunochemotherapy varies, with mostly a fatal outcome in cases of resistant disease. Here, we show that lymphoma exosomes shield target cells from antibody attack and that exosome biogenesis is modulated by the lysosome-related organelle-associated ATP-binding cassette (ABC) transporter A3 (ABCA3). B-cell lymphoma cells released exosomes that carried CD20, bound therapeutic anti-CD20 antibodies, consumed complement, and protected target cells from antibody attack. ABCA3, previously shown to mediate resistance to chemotherapy, was critical for the amounts of exosomes released, and both pharmacological blockade and the silencing of ABCA3 enhanced susceptibility of target cells to antibody-mediated lysis. Mechanisms of cancer cell resistance to drugs and antibodies are linked in an ABCA3-dependent pathway of exosome secretion.
The intensity of the conditioning regimen given before allogeneic hematopoietic cell transplantation (allo-HCT) can vary substantially. To confirm the ability of the recently developed transplant ...conditioning intensity (TCI) score to stratify the preparative regimens of allo-HCT, we used an independent and contemporary patient cohort of 4060 transplant recipients with acute myeloid leukemia meeting inclusion criteria from the discovery study (allo-HCT in first complete remission, matched donor), but who were allografted in a more recent period (2018-2021) and were one decade older (55-75 years, median 63.4 years), we assigned them to a TCI category (low n = 1934, 48%; intermediate n = 1948, 48%, high n = 178, 4%) according to the calculated TCI score (1-2, 2.5-3.5, 4-6, respectively), and examined the validity of the TCI category in predicting early non-relapse mortality (NRM), 2-year NRM and relapse (REL). In the unadjusted comparison, the TCI index provided a significant risk stratification for d100 and d180 NRM, NRM and REL risk. In the multivariate analysis adjusted for significant variables, there was an independent association of TCI with early NRM, NRM and REL. In summary, we confirm in contemporary treated patients that TCI reflects the conditioning regimen related morbidity and anti-leukemic efficacy satisfactorily and across other established prognostic factors.
PTCL patients exhibit poor survival with existing treatments. We investigated the efficacy of CHOP combined with alemtuzumab in 116 PTCL patients age 61-80 in an open-label, randomized phase 3 trial. ...Alemtuzumab was given on day 1, to a total of 360 mg in 21 patients, or 120 mg in 37. Hematotoxicity was increased with A-CHOP resulting in more grade ≥3 infections (40% versus 21%) and 4 versus 1 death due to infections, respectively. CR/CRu rate was 60% for A-CHOP and 43% for CHOP, and OR rate was 72% and 66%, respectively. Three-year-EFS, PFS and OS were 27% 15%-39%, 28% 15%-40%, and 37% (23%-50% for A-CHOP, and 24% 12%-35%, 29% 17%-41%, and 56% 44%-69% for CHOP, respectively, showing no significant differences. Multivariate analyses, adjusted for strata and sex confirmed these results (hazard ratio HR
: 0.7 (95% CI: 0.5-1.1; p = 0.094), HR
: 0.8 (95% CI: 0.5-1.2; p = 0.271), HR
: 1.4 (95% CI: 0.9-2.4; p = 0.154). The IPI score was validated, and male sex (HR
2.5) and bulky disease (HR
2.2) were significant risk factors for EFS, PFS, and OS. Alemtuzumab added to CHOP increased response rates, but did not improve survival due to treatment-related toxicity.
Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined ...activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.
For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PD‐like syndromes. However, the mechanisms of ...Mn toxicity are still poorly understood. Here, we demonstrate that Mn dose‐ and time‐dependently blocks the protein translation of amyloid precursor protein (APP) and heavy‐chain Ferritin (H‐Ferritin), both iron homeostatic proteins with neuroprotective features. APP and H‐Ferritin are post‐transcriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5′‐untranslated regions (5′‐UTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5′‐UTR‐activity of APP and H‐Ferritin, presumably via increased iron responsive proteins‐iron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe2+‐specific probes (RhoNox‐1 and IP‐1) and ion chromatography inductively coupled plasma mass spectrometry (IC‐ICP‐MS), we show that loss of the protective axis of APP and H‐Ferritin resulted in unchecked accumulation of redox‐active ferrous iron (Fe2+) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mn‐induced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mn‐mediated suppression of APP and H‐Ferritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mn‐induced neurotoxicity is partly attributable to the translational inhibition of APP and H‐Ferritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress.
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For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PD‐like syndromes. Here, we demonstrate that Mn exposure results in suppression of amyloid precursor protein (APP) and H‐Ferritin in vitro and in vivo. On the molecular level, it could be shown that Mn inhibits the protein translation via repressing the 5’‐UTR activity of both proteins. Mn‐mediated suppression of both iron‐regulating proteins results in an accumulation of redox‐active iron (Fe2+) that fuels neurotoxic cellular oxidative stress and lipidperoxidation. APP overexpression significantly attenuate Mn‐induced oxidative stress and neurotoxicity. The implications that Mn exposure results in a translational suppression of APP and H‐Ferritin links a disturbed iron homeostasis with Mn‐induced oxidative neurotoxicity.
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Although R-CHOP-based immunochemotherapy cures significant proportions of patients with aggressive B-cell lymphoma, tumor cell susceptibility to chemotherapy varies, with mostly fatal outcome in ...cases of resistant disease. We and others have shown before that export of cytostatic drugs contributes to drug resistance. Now we provide a novel approach to overcome exosome-mediated drug resistance in aggressive B-cell lymphomas.
We used well-established centrifugation protocols to purify exosomes from DLBCL cell lines and detected anthracyclines using FACS and HPLC. We used shRNA knockdown of ABCA3 to determine ABCA3 dependence of chemotherapy susceptibility and monitored ABCA3 expression after indomethacin treatment using qPCR. Finally, we established an in vivo assay using a chorioallantoic membrane (CAM) assay to determine the synergy of anthracycline and indomethacin treatment.
We show increased efficacy of the anthracycline doxorubicin and the anthracenedione pixantrone by suppression of exosomal drug resistance with indomethacin. B-cell lymphoma cells in vitro efficiently extruded doxorubicin and pixantrone, in part compacted in exosomes. Exosomal biogenesis was critically dependent on the expression of the ATP-transporter A3 (ABCA3). Genetic or chemical depletion of ABCA3 augmented intracellular retention of both drugs and shifted the subcellular drug accumulation to prolonged nuclear retention. Indomethacin increased the cytostatic efficacy of both drugs against DLBCL cell lines in vitro and in vivo in a CAM assay.
We propose pretreatment with indomethacin toward enhanced antitumor efficacy of anthracyclines and anthracenediones.
Tumors are composed of phenotypically heterogeneous cell populations. The nongenomic mechanisms underlying transitions and interactions between cell populations are largely unknown. Here, we show ...that diffuse large B-cell lymphomas possess a self-organized infrastructure comprising side population (SP) and non-SP cells, where transitions between clonogenic states are modulated by exosome-mediated Wnt signaling. DNA methylation modulated SP–non-SP transitions and was correlated with the reciprocal expressions of Wnt signaling pathway agonist Wnt3a in SP cells and the antagonist secreted frizzled-related protein 4 in non-SP cells. Lymphoma SP cells exhibited autonomous clonogenicity and exported Wnt3a via exosomes to neighboring cells, thus modulating population equilibrium in the tumor.
•Diffuse large B-cell lymphomas are composed of clonogenic side population (SP) cells and non-SP cells organized in a dynamic equilibrium.•Exosome-mediated Wnt signaling modulates transitions of cell states and tumor progression amenable to drug targeting.
To validate current donor selection strategies based on previous international studies, we retrospectively analyzed 2646 transplantations performed for hematologic malignancies in 28 German ...transplant centers. Donors and recipients were high resolution typed for HLA-A, -B, -C, -DRB1, and -DQB1. The highest mortality in overall survival analysis was seen for HLA-A, -B, and DRB1 mismatches. HLA-DQB1 mismatched cases showed a trend toward higher mortality, mostly due to HLA-DQB1 antigen disparities. HLA incompatibilities at >1 locus showed additive detrimental effects. HLA mismatching had no significant effect on relapse incidence and primary graft failure. Graft source had no impact on survival end points, neither in univariate nor in multivariate analysis. Higher patient age, advanced disease, transplantations before 2004, patient C2C2 killer cell immunoglobulin-like receptor (KIR)-ligand phenotype, and unavailability of a national donor adversely influenced outcomes in multivariate analysis. Our study confirms the association of HLA-A, -B, -C, and -DRB1 incompatibilities with adverse outcome in hematopoietic stem cell transplantation (HSCT). The relevance of HLA-DQB1 disparities in single mismatched transplantations remains unclear. Similar hazard ratios for allele and antigen mismatches (possibly with an exception for HLA-DQB1) highlight the importance of allele level typing and matching in HSCT. The number of incompatibilities and their type significantly impact survival.
•HLA mismatches at the allele and antigen level (possibly with the exception of HLA-DQB1) should be treated equally in donor selection.•HLA mismatches at >1 locus (including HLA-DQB1) have additive detrimental effects.
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