| 1. |
- Abé, Christoph, et al.
(författare)
-
Cytarabine dose intensification improves survival in older patients with secondary/high-risk acute myeloid leukemia in matched real-world versus clinical trial data
- 2024
-
Ingår i: Leukemia and Lymphoma. - 1042-8194 .- 1029-2403.
-
Tidskriftsartikel (refereegranskat)abstract
- Since 1980’s, the established/standard treatment of acute myeloid leukemia (AML) is cytarabine infusion with anthracycline (7 + 3 regimen). We compared the 7 + 3 regimen in older secondary/high-risk AML patientsfrom a clinical trial with a matched population from the Swedish AML Registrytreated withan increased cytarabine dose in induction and consolidation as recommended in the Swedish National Guidelines since 2005. After successfulpropensity score matching, 104 patients per group were included. The primary outcome was overall survival (OS), and standard dosed patients had a median OS of 6.4 versus 10.7 months with increased dose intensity (hazard ratio:0.69, p = 0.012), with 5-year OS of 8.7% and 18.1%, andremission rates of 36% and 60%, respectively (p < 0.001). Median OS after allogeneic hematopoietic cell transplantation (in 27.9% per group) was 10.4 and 20.7 months, respectively. We conclude that the more intensive cytarabine schedule seems to provide improved outcomes inthe investigated AML patient group.
|
|
| 2. |
- Al Agrafi, Faisal, et al.
(författare)
-
Selective lysis of acute myeloid leukemia cells by CD34/CD3 bispecific antibody through the activation of γδ T-cells
- 2024
-
Ingår i: Oncoimmunology. - : Taylor and Francis Ltd.. - 2162-4011 .- 2162-402X. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Despite the considerable progress in acute myeloid leukemia (AML) treatment, relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is still frequent and associated with a poor prognosis. Relapse has been shown to be correlated with an incomplete eradication of CD34+ leukemic stem cells prior to HSCT. Previously, we have shown that a novel CD34-directed, bispecific T-cell engager (BTE) can efficiently redirect the T-cell effector function toward cancer cells, thus eliminating leukemic cells in vitro and in vivo. However, its impact on γδ T-cells is still unclear. In this study, we tested the efficacy of the CD34-specific BTE using in vitro expanded γδ T-cells as effectors. We showed that the BTEs bind to γδ T-cells and CD34+ leukemic cell lines and induce target cell killing in a dose-dependent manner. Additionally, γδ T-cell mediated killing was found to be superior to αβ T-cell mediated cytotoxicity. Furthermore, we observed that only in the presence of BTE the γδ T-cells induced primary AML blast killing in vitro. Importantly, our results show that γδ T-cells did not target the healthy CD34intermediate endothelial blood–brain barrier cell line (hCMEC/D3) nor lysed CD34+ HSCs from healthy bone marrow samples.
|
|
| 3. |
- Ali, Dina, et al.
(författare)
-
Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells
- 2016
-
Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 174:1, s. 117-126
-
Tidskriftsartikel (refereegranskat)abstract
- The small molecule APR-246 (PRIMA-1(MET)) is a novel drug that restores the activity of mutated and unfolded TP53 protein. However, the mechanisms of action and potential off-target effects are not fully understood. Gene expression profiling in TP53 mutant KMB3 acute myeloid leukaemia (AML) cells showed that genes which protected cells from oxidative stress to be the most up-regulated. APR-246 exposure also induced reactive oxygen species (ROS) formation and depleted glutathione in AML cells. The genes most up-regulated by APR-246, confirmed by quantitative real time polymerase chain reaction, were heme oxygenase-1 (HMOX1, also termed HO-1), SLC7A11 and RIT1. Up-regulation of HMOX1, a key regulator of cellular response to ROS, was independent of TP53 mutational status. NFE2L2 (also termed Nrf2), a master regulator of HMOX1 expression, showed transcriptional up-regulation and nuclear translocation by APR-246. Down-regulation of NFE2L2 by siRNA in AML cells significantly increased the antitumoural effects of APR-246. The PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin inhibited APR-246-induced nuclear translocation of NFE2L2 and counteracted the protective cellular responses to APR-246, resulting in synergistic cell killing together with APR-246. In conclusion, ROS induction is important for antileukaemic activities of APR-246 and inhibiting the protective response of the Nrf-2/HMOX1 axis using PI3K inhibitors, enhances the antileukaemic effects.
|
|
| 4. |
- Ali, M, et al.
(författare)
-
T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes
- 2022
-
Ingår i: Nature biotechnology. - : Springer Science and Business Media LLC. - 1546-1696 .- 1087-0156. ; 40:4, s. 488-
-
Tidskriftsartikel (refereegranskat)abstract
- Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.
|
|
| 5. |
- Anande, Govardhan, et al.
(författare)
-
RNA Splicing Alterations Induce a Cellular Stress Response Associated with Poor Prognosis in Acute Myeloid Leukemia
- 2020
-
Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 26:14, s. 3597-3607
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: RNA splicing is a fundamental biological process that generates protein diversity from a finite set of genes. Recurrent somatic mutations of splicing factor genes are common in some hematologic cancers but are relatively uncommon in acute myeloid leukemia (AML, < 20% of patients). We examined whether RNA splicing differences exist in AML, even in the absence of splicing factor mutations.Experimental Design: We developed a bioinformatics pipeline to study alternative RNA splicing in RNA-sequencing data from large cohorts of patients with AML.Results: We have identified recurrent differential alternative splicing between patients with poor and good prognosis. These splicing events occurred even in patients without any discernible splicing factor mutations. Alternative splicing recurrently occurred in genes with specific molecular functions, primarily related to protein translation. Developing tools to predict the functional impact of alternative splicing on the translated protein, we discovered that approximately 45% of the splicing events directly affected highly conserved protein domains. Several splicing factors were themselves misspliced and the splicing of their target transcripts were altered. Studying differential gene expression in the same patients, we identified that alternative splicing of protein translation genes in ELNAdv patients resulted in the induction of an integrated stress response and upregulation of inflammation-related genes. Finally, using machine learning techniques, we identified a splicing signature of four genes which refine the accuracy of existing risk prognosis schemes and validated it in a completely independent cohort.Conclusions: Our discoveries therefore identify aberrant alternative splicing as a molecular feature of adverse AML with clinical relevance.
|
|
| 6. |
- Angenendt, Linus, et al.
(författare)
-
Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia : A Pooled Analysis of Individual Patient Data From Nine International Cohorts
- 2019
-
Ingår i: Journal of Clinical Oncology. - : AMER SOC CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 37:29, s. 2632-2642
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.METHODS: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1(mut)/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.RESULTS: Among 2,426 patients with NPM1(mut)/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1(mut)/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome.CONCLUSION: Karyotype abnormalities are significantly associated with outcome in NPM1(mut)/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1(mut) share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1(mut)/FLT3-ITDneg/low AML.
|
|
| 7. |
- Antonelli, Alexandre, 1978, et al.
(författare)
-
Madagascar's extraordinary biodiversity : Evolution, distribution, and use
- 2022
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 378:6623, s. 962-
-
Tidskriftsartikel (refereegranskat)abstract
- Madagascar's biota is hyperdiverse and includes exceptional levels of endemicity. We review the current state of knowledge on Madagascar's past and current terrestrial and freshwater biodiversity by compiling and presenting comprehensive data on species diversity, endemism, and rates of species description and human uses, in addition to presenting an updated and simplified map of vegetation types. We report a substantial increase of records and species new to science in recent years; however, the diversity and evolution of many groups remain practically unknown (e.g., fungi and most invertebrates). Digitization efforts are increasing the resolution of species richness patterns and we highlight the crucial role of field- and collections-based research for advancing biodiversity knowledge and identifying gaps in our understanding, particularly as species richness corresponds closely to collection effort. Phylogenetic diversity patterns mirror that of species richness and endemism in most of the analyzed groups. We highlight humid forests as centers of diversity and endemism because of their role as refugia and centers of recent and rapid radiations. However, the distinct endemism of other areas, such as the grassland-woodland mosaic of the Central Highlands and the spiny forest of the southwest, is also biologically important despite lower species richness. The documented uses of Malagasy biodiversity are manifold, with much potential for the uncovering of new useful traits for food, medicine, and climate mitigation. The data presented here showcase Madagascar as a unique " living laboratory" for our understanding of evolution and the complex interactions between people and nature. The gathering and analysis of biodiversity data must continue and accelerate if we are to fully understand and safeguard this unique subset of Earth's biodiversity.
|
|
| 8. |
- Berggren, Daniel Moreno, et al.
(författare)
-
Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting : a report from the Swedish MDS register
- 2018
-
Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 181:5, s. 614-627
-
Tidskriftsartikel (refereegranskat)abstract
- The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2.9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P < 0001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0.05) and for WPSS compared to IPSS (P=0.07). IPSS-R was superior to both IPSS and WPSS for patients aged <= 70years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power.
|
|
| 9. |
- Castell, Alina, et al.
(författare)
-
MYCMI-7 : A Small MYC-Binding Compound that Inhibits MYC: MAX Interaction and Tumor Growth in a MYC-Dependent Manner
- 2022
-
Ingår i: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 2:3, s. 182-201
-
Tidskriftsartikel (refereegranskat)abstract
- Deregulated expression of MYC family oncogenes occurs frequently in human cancer and is often associated with aggressive disease and poor prognosis. While MYC is a highly warranted target, it has been considered "undruggable," and no specific anti-MYC drugs are available in the clinic. We recently identified molecules named MYCMIs that inhibit the interaction between MYC and its essential partner MAX. Here we show that one of these molecules, MYCMI-7, efficiently and selectively inhibits MYC:MAX and MYCN:MAX interactions in cells, binds directly to recombinant MYC, and reduces MYC-driven transcription. In addition, MYCMI-7 induces degradation of MYC and MYCN proteins. MYCMI-7 potently induces growth arrest/apoptosis in tumor cells in a MYC/MYCN-dependent manner and downregulates the MYC pathway on a global level as determined by RNA sequencing. Sensitivity to MYCMI-7 correlates with MYC expression in a panel of 60 tumor cell lines and MYCMI-7 shows high efficacy toward a collection of patient-derived primary glioblastoma and acute myeloid leukemia (AML) ex vivo cultures. Importantly, a variety of normal cells be- come G1 arrested without signs of apoptosis upon MYCMI-7 treatment. Finally, in mouse tumor models of MYC-driven AML, breast cancer, and MYCN-amplified neuroblastoma, treatment with MYCMI-7 downregu- lates MYC/MYCN, inhibits tumor growth, and prolongs survival through apoptosis with few side effects. In conclusion, MYCMI-7 is a potent and selective MYC inhibitor that is highly relevant for the development into clinically useful drugs for the treatment of MYC-driven cancer.Significance: Our findings demonstrate that the small-molecule MYCMI-7 binds MYC and inhibits interaction between MYC and MAX, thereby ham- pering MYC-driven tumor cell growth in culture and in vivo while sparing normal cells.
|
|
| 10. |
- Castor, Anders, et al.
(författare)
-
Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia
- 2005
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 11:6, s. 630-637
-
Tidskriftsartikel (refereegranskat)abstract
- The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.
|
|
