Browsing by Subject "ACUTE MYELOID-LEUKEMIA"

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  • Cremers, Eline M. P.; de Witte, Theo; de Wreede, Liesbeth; Eikema, Diderik-Jan; Koster, Linda; van Biezen, Anja; Finke, Jurgen; Socie, Gerard; Beelen, Dietrich; Maertens, Johan; Nagler, Arnon; Kobbe, Guido; Ziagkos, Dimitris; Itälä-Remes, Maija; Gedde-Dahl, Tobias; Sierra, Jorge; Niederwieser, Dietger; Ljungman, Per; Beguin, Yves; Ozkurt, Zubeyde Nur; Anagnostopoulos, Achilles; Jindra, Pavel; Robin, Marie; Kröger, Nicolaus (2019)
    Most myelodysplastic syndromes (MDS)-patients receive multiple red blood cell transfusions (RBCT). Transfusions may cause iron-related toxicity and mortality, influencing outcome after allogeneic HSCT. This prospective non-interventional study evaluated 222 MDS and CMML patients undergoing HSCT. Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), and relapse incidence (RI) at 36 months were 52%, 44%, 25%, and 31%, respectively. Age, percentage of marrow blasts and severe comorbidities impacted OS. RFS was significantly associated with RBCT burden prior to HSCT (HR: 1.7; p = .02). High ferritin levels had a significant negative impact on OS and RI, but no impact on NRM. Administration of iron chelation therapy prior to HSCT did not influence the outcome, but early iron reduction after HSCT (started before 6 months) improved RFS significantly after transplantation (56% in the control group vs. 90% in the treated group, respectively; p = .04). This study illustrates the impact of RBCT and related parameters on HSCT-outcome. Patients with an expected prolonged survival after transplantation may benefit from early iron reduction therapy after transplantation.
  • Schrader, A.; Crispatzu, G.; Oberbeck, S.; Mayer, P.; Pützer, S.; von Jan, J.; Vasyutina, E.; Warner, K.; Weit, N.; Pflug, N.; Braun, T.; Andersson, E. I.; Yadav, B.; Riabinska, A.; Maurer, B.; Ferreira, M. S. Ventura; Beier, F.; Altmueller, J.; Lanasa, M.; Herling, C. D.; Haferlach, T.; Stilgenbauer, S.; Hopfinger, G.; Peifer, M.; Brümmendorf, T. H.; Nürnberg, P.; Elenitoba-Johnson, K. S. J.; Zha, S.; Hallek, M.; Moriggl, R.; Reinhardt, H. C.; Stern, M. -H.; Mustjoki, S.; Newrzela, S.; Frommolt, P.; Herling, M. (2018)
    T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.
  • Baron, Frederic; Galimard, Jacques-Emmanue; Labopin, Myriam; Yakoub-Agha, Ibrahim; Niittyvuopio, Riitta; Kroeger, Nicolaus; Griskevicius, Laimonas; Wu, Depei; Forcade, Edouard; Richard, Carlos; Aljurf, Mahmoud; Helbig, Grzegorz; Labussiere-Wallet, Helene; Mohty, Mohamad; Nagler, Arnon (2020)
    We compared severe graft-versus-host-disease GyHD) free and relapse-free survival and other transplantation outcomes of acute myeloid leukemia (AML) patients given bone marrow (BM) without and-thymocyte globulin (ATG) versus peripheral blood stem cells (PBSC) with ATG after myeloablative conditioning. In the cohort of patients receiving grafts from a human leukocyte antigen (HLA)-matched sibling donor, patients given PBSC with ATG (n=1,021) and those given BM without ATG (n=1,633) presented comparable severe GvHD-free relapse-free survival (GRSF)(hazard ratio [HR]=0.9, 95% confidence interval [CI]: 0.8-1.1, P=0.5) and overall survival (HR=1.0, 95% CI: 0.8-1.2, P=0.8). They had however, a lower incidence of chronic GvHD (cGvHD) (HR=0.7, 95% CI: 0.6-0.9, P=0.01). In the cohort of patients receiving grafts from HLA-matched unrelated donor , patients given PBSC with ATG (n=2,318) had better severe GvHD-free and relapse-free survival (GRFS) than those given BM without ATG (n=303) (HR=0.8, 95% CI: 0.6-0.9, P=0.001). They also had a lower incidence of cGvHD (HR=0.6, 95% CI: 0.5-0.8, P=0.0006) and better overall survival (HR=0.8, 95% CI: 0.6-1.0, P=0.04). In summary, these data suggest that PBSC with ATG results in comparable (in the case of sibling donor) or significantly better (in the case of unrelated donor) severe GRFS than BM without ATG in patients with AML in complete remission receiving grafts after myeloablative conditioning.
  • Halaburda, Kazimierz; Labopin, Myriam; Houhou, Mohamed; Niederwieser, Dietger; Finke, Juergen; Volin, Liisa; Maertens, Johan; Cornelissen, Jan J.; Milpied, Noel; Stuhler, Gernot; Kroeger, Nicolaus; Esteve, Jordi; Mohty, Mohamad; Nagler, Arnon (2018)
    Acute myeloid leukemia with inv(3)(q21;q26.2)/t(3;3)(q21;q26.2) (3q26 AML) is a rare disease with poor prognosis and median survival of
  • Singh, Abhishek A.; Mandoli, Amit; Prange, Koen H. M.; Laakso, Marko; Martens, Joost H. A. (2017)
    Chromosomal translocations are one of the hallmarks of acute myeloid leukemia (AML), often leading to gene fusions and expression of an oncofusion protein. Over recent years it has become clear that most of the AML associated oncofusion proteins molecularly adopt distinct mechanisms for inducing leukemogenesis. Still these unique molecular properties of the chimeric proteins converge and give rise to a common pathogenic molecular mechanism. In the present study we compared genome-wide DNA binding and transcriptome data associated with AML1-ETO, CBFB-MYH11 and PML-RARA oncofusion protein expression to identify unique and common features. Our analyses revealed targeting of oncofusion binding sites to RUNX1 and ETS-factor occupied genomic regions. In addition, it revealed a highly comparable global histone acetylation pattern, similar expression of common target genes and related enrichment of several biological pathways critical for maintenance of AML, suggesting oncofusion proteins deregulate common gene programs despite their distinct binding signatures and mechanisms of action.
  • Penack, Olaf; Peczynski, Christophe; van der Werf, Steffie; Finke, Juergen; Ganser, Arnold; Schoemans, Helene; Pavlu, Jiri; Niittyvuopio, Riitta; Schroyens, Wilfried; Kaynar, Leylagul; Blau, Igor W.; van der Velden, Walter J. F. M.; Sierra, Jorge; Cortelezzi, Agostino; Wulf, Gerald; Turlure, Pascal; Rovira, Montserrat; Ozkurt, Zubeydenur; Pascual-Cascon, Maria J.; Moreira, Maria C.; Clausen, Johannes; Greinix, Hildegard; Duarte, Rafael F.; Basak, Grzegorz W. (2020)
    Elevated serum ferritin levels occur due to iron overload or during inflammation and macrophage activation. A correlation of high serum ferritin levels with increased mortality after alloSCT has been suggested by several retrospective analyses as well as by two smaller prospective studies. This prospective multicentric study aimed to study the association of ferritin serum levels before start of conditioning with alloSCT outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling alloSCT for the first time were considered for inclusion, regardless of conditioning. A comparison of outcomes between patients with high and low ferritin level was performed using univariate analysis and multivariate analysis using cause-specific Cox model. Twenty centers reported data on 298 alloSCT recipients. The ferritin cut off point was determined at 1500 mu g/l (median of measured ferritin levels). In alloSCT recipients with ferritin levels above cut off measured before the start of conditioning, overall survival (HR = 2.5, CI = 1.5-4.1, p = 0.0005) and progression-free survival (HR = 2.4, CI = 1.6-3.8, p <0.0001) were inferior. Excess mortality in the high ferritin group was due to both higher relapse incidence (HR = 2.2, CI = 1.2-3.8, p = 0.007) and increased non-relapse mortality (NRM) (HR = 3.1, CI = 1.5-6.4, p = 0.002). NRM was driven by significantly higher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6-9.7, p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT.
  • Duque-Afonso, Jesus; Finke, Jürgen; Labopin, Myriam; Craddock, Charles; Protheroe, Rachel; Kottaridis, Panagiotis; Tholouli, Eleni; Byrne, Jenny L.; Orchard, Kim; Salmenniemi, Urpu; Hilgendorf, Inken; Hunter, Hannah; Nicholson, Emma; Bloor, Adrian; Snowden, John A.; Verbeek, Mareike; Clark, Andrew; Savani, Bipin N.; Spyridonidis, Alexandros; Nagler, Arnon; Mohty, Mohamad (2022)
    In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m(2) (FluMel) and fludarabine/treosulfan 42 g/m(2) (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.
  • Tobiasson, Magnus; Abdulkadir, Hani; Lennartsson, Andreas; Katayama, Shintaro; Marabita, Francesco; De Paepe, Ayla; Karimi, Mohsen; Krjutskov, Kaarel; Einarsdottir, Elisabet; Grovdal, Michael; Jansson, Monika; Ben Azenkoud, Asmaa; Corddedu, Lina; Lehmann, Soren; Ekwall, Karl; Kere, Juha; Hellstrom-Lindberg, Eva; Ungerstedt, Johanna (2017)
    Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median beta-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.
  • Deng, Shan; Yang, Xiaojun; Lassus, Heini; Liang, Shun; Kaur, Sippy; Ye, Qunrui; Li, Chunsheng; Wang, Li-Ping; Roby, Katherine F.; Orsulic, Sandra; Connolly, Denise C.; Zhang, Youcheng; Montone, Kathleen; Butzow, Ralf; Coukos, George; Zhang, Lin (2010)
  • Borssen, Magnus; Haider, Zahra; Landfors, Mattias; Noren-Nystrom, Ulrika; Schmiegelow, Kjeld; Asberg, Ann E.; Kanerva, Jukka; Madsen, Hans O.; Marquart, Hanne; Heyman, Mats; Hultdin, Magnus; Roos, Goran; Forestier, Erik; Degerman, Sofie (2016)
    Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making. (C) 2016 Wiley Periodicals, Inc.
  • Tanoli, ZiaurRehman; Alam, Zaid; Vähä-Koskela, Markus; Ravikumar, Balaguru; Malyutina, Alina; Jaiswal, Alok; Tang, Jing; Wennerberg, Krister; Aittokallio, Tero (2018)
    Drug Target Commons (DTC) is a web platform (database with user interface) for community-driven bioactivity data integration and standardization for comprehensive mapping, reuse and analysis of compound-target interaction profiles. End users can search, upload, edit, annotate and export expert-curated bioactivity data for further analysis, using an application programmable interface, database dump or tab-delimited text download options. To guide chemical biology and drug-repurposing applications, DTC version 2.0 includes updated clinical development information for the compounds and target gene-disease associations, as well as cancer-type indications for mutant protein targets, which are critical for precision oncology developments.
  • Malani, D.; Murumagi, A.; Yadav, B.; Kontro, M.; Eldfors, S.; Kumar, A.; Karjalainen, R.; Majumder, M. M.; Ojamies, P.; Pemovska, T.; Wennerberg, K.; Heckman, C.; Porkka, K.; Wolf, M.; Aittokallio, T.; Kallioniemi, O. (2017)
    We sought to identify drugs that could counteract cytarabine resistance in acute myeloid leukemia (AML) by generating eight resistant variants from MOLM-13 and SHI-1 AML cell lines by long-term drug treatment. These cells were compared with 66 ex vivo chemorefractory samples from cytarabine-treated AML patients. The models and patient cells were subjected to genomic and transcriptomic profiling and high-throughput testing with 250 emerging and clinical oncology compounds. Genomic profiling uncovered deletion of the deoxycytidine kinase (DCK) gene in both MOLM-13- and SHI-1-derived cytarabine-resistant variants and in an AML patient sample. Cytarabine-resistant SHI-1 variants and a subset of chemorefractory AML patient samples showed increased sensitivity to glucocorticoids that are often used in treatment of lymphoid leukemia but not AML. Paired samples taken from AML patients before treatment and at relapse also showed acquisition of glucocorticoid sensitivity. Enhanced glucocorticoid sensitivity was only seen in AML patient samples that were negative for the FLT3 mutation (P = 0.0006). Our study shows that development of cytarabine resistance is associated with increased sensitivity to glucocorticoids in a subset of AML, suggesting a new therapeutic strategy that should be explored in a clinical trial of chemorefractory AML patients carrying wild-type FLT3.
  • Liljavirta, Jenni; Niku, Mikael; Pessa-Morikawa, Tiina; Ekman, Anna; Iivanainen, Antti (2014)
  • Ronkko, R; Hirvonen, E; Malila, N; Kilpivaara, O; Wartiovaara-Kautto, U; Pitkaniemi, J (2021)
    Population-based studies on familial aggregation of haematological malignancies (HM) have rarely focused specifically on early-onset HMs. We estimated standardized incidence ratios (SIR) and cumulative risks of relatives with Hodgkin lymphoma (HL), non-Hodgkin lymphomas (NHL), acute lymphoblastic leukaemia/lymphoma (ALL/LBL) and acute myeloid leukaemia (AML) when index persons and relatives were diagnosed with early-onset HM. A total of 8791 patients aged
  • Pölönen, Petri; Mehtonen, Juha; Lin, Jake; Liuksiala, Thomas; Häyrynen, Sergei; Teppo, Susanna; Mäkinen, Artturi; Kumar, Ashwini; Malani, Disha; Pohjolainen, Virva; Porkka, Kimmo; Heckman, Caroline A.; May, Patrick; Hautamäki, Ville; Granberg, Kirsi J.; Lohi, Olli; Nykter, Matti; Heinäniemi, Merja (2019)
    Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease context for new therapeutic approaches. We analyzed 9,544 transcriptomes from more than 30 hematologic malignancies, normal blood cell types, and cell lines, and showed that disease types could be stratified in a data-driven manner. We then identified cluster-specific pathway activity, new biomarkers, and in silico drug target prioritization through interrogation of drug target databases. Using known vulnerabilities and available drug screens, we highlighted the importance of integrating molecular phenotype with drug target expression for in silico prediction of drug responsiveness. Our analysis implicated BCL2 expression level as an important indicator of venetoclax responsiveness and provided a rationale for its targeting in specific leukemia subtypes and multiple myeloma, linked several polycomb group proteins that could be targeted by small molecules (SFMBT1, CBX7, and EZH1) with chronic lymphocytic leukemia, and supported CDK6 as a disease-specific target in acute myeloid leukemia. Through integration with proteomics data, we characterized target protein expression for pre-B leukemia immunotherapy candidates, including DPEP1. These molecular data can be explored using our publicly available interactive resource, Hemap, for expediting therapeutic innovations in hematologic malignancies.
  • Giri, Anil K.; Ianevski, Aleksander (2022)
    Introduction The interactions between leukemic blasts and cells within the bone marrow environment affect oncogenesis, cancer stem cell survival, as well as drug resistance in hematological cancers. The importance of this interaction is increasingly being recognized as a potentially important target for future drug discoveries and developments. Recent innovations in the high throughput drug screening-related technologies, novel ex-vivo disease-models, and freely available machine-learning algorithms are advancing the drug discovery process by targeting earlier undruggable proteins, complex pathways, as well as physical interactions (e.g. leukemic cell-bone microenvironment interaction). Area covered In this review, the authors discuss the recent methodological advancements and existing challenges to target specialized hematopoietic niches within the bone marrow during leukemia and suggest how such methods can be used to identify drugs targeting leukemic cell-bone microenvironment interactions. Expert opinion The recent development in cell-cell communication scoring technology and culture conditions can speed up the drug discovery by targeting the cell-microenvironment interaction. However, to accelerate this process, collecting clinical-relevant patient tissues, developing culture model systems, and implementing computational algorithms, especially trained to predict drugs and their combination targeting the cancer cell-bone microenvironment interaction are needed.
  • Nagler, Arnon; Labopin, Myriam; Dholaria, Bhagirathbhai; Niittyvuopio, Riitta; Maertens, Johan; Poire, Xavier; Cornelissen, Jan; Remenyi, Peter; Bourhis, Jean Henri; Beguin, Yves; Malladi, Ram; Kerre, Tessa; Schroyens, Wilfried; Savani, Bipin N.; Mohty, Mohamad (2019)
    The impact of the use of antithymocyte globulin (ATG) following a total body irradiation (TBI)-based myeloablative conditioning regimen has been poorly explored. We retrospectively analyzed 724 patients who underwent a first allogeneic hematopoietic cell transplantation (allo-HCT) following a TBI-based conditioning regimen for acute myeloid leukemia (AML) and compared the outcomes of 251 (35%) patients who received ATG (ATG group) with 473 (65%) patients who did not (non-ATG group). Median follow-up of surviving patients was 59 months (interquartile range, 28-83). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) for non-ATG and ATG groups in the first 100 days was 33% vs 24%, respectively (P = .0098). The 2-year cumulative incidence of chronic graft-versus-host disease (cGVHD) was reduced significantly in the ATG group in comparison with the non-ATG group (46% vs 34%, P = .003). Using multivariate analysis, in vivo T-cell depletion (ATG group) was independently associated with a decreased incidence of grade II-IV aGVHD (hazard ratio [HR], 0.28; P <.001), grade III-IV aGVHD (HR, 0.21; P <.001), cGVHD (HR, 0.63; P = .02), and nonrelapse mortality (NRM) (HR, 0.54; P = .02). Relapse risk, overall survival, and leukemia-free survival were similar between the 2 groups. Our results suggest that the addition of ATG to TBI-based myeloablative conditioning for allo-HCT in AML patients results in a significant reduction in aGVHD and cGVHD, translating into a significant reduction in NRM without increasing the relapse rate.
  • Brown, Rachel E.; Jacobse, Justin; Anant, Shruti A.; Blunt, Koral M.; Chen, Bob; Vega, Paige N.; Jones, Chase T.; Pilat, Jennifer M.; Revetta, Frank; Gorby, Aidan H.; Stengel, Kristy R.; Choksi, Yash A.; Palin, Kimmo; Piazuelo, M. Blanca; Washington, Mary Kay; Lau, Ken S.; Goettel, Jeremy A.; Hiebert, Scott W.; Short, Sarah P.; Williams, Christopher S. (2022)
    Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (iBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium-induced (DSS-induced) colitis. Transcriptomic analyses implicated increased Ephrussi box-binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a mouse model with a point mutation that attenuates MTG16:E protein interactions (Mtg16(P20ST)), we showed that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein-mediated transcription. Mimicking murine colitis, MTG16 expression was increased in biopsies from patients with active IBD compared with unaffected controls. Finally, uncoupling MTG16:E protein interactions partially phenocopied the enhanced tumorigenicity of Mtg16(-/)(-) colon in the azoxymethane/DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Collectively, our results demonstrate that MTG16, via its repression of E protein targets. is a key regulator of cell fate decisions during colon homeostasis, colitis, and cancer.
  • Majumder, Muntasir M.; Leppä, Aino-Maija; Hellesøy, Monica; Dowling, Paul; Malyutina, Alina; Kopperud, Reidun; Bazou, Despina; Andersson, Emma; Parsons, Alun; Tang, Jing; Kallioniemi, Olli; Mustjoki, Satu; O´Gorman, Peter; Wennerberg, Krister; Porkka, Kimmo; Gjertsen, Bjørn T.; Heckman, Caroline A. (2020)
    Innate drug sensitivity in healthy cells aids identification of lineage specific anti-cancer therapies and reveals off-target effects. To characterize the diversity in drug responses in the major hematopoietic cell types, we simultaneously assessed their sensitivity to 71 small molecules utilizing a multi-parametric flow cytometry assay and mapped their proteomic and basal signaling profiles. Unsupervised hierarchical clustering identified distinct drug responses in healthy cell subsets based on their cellular lineage. Compared to other cell types, CD19+/B and CD56+/NK cells were more sensitive to dexamethasone, venetoclax and midostaurin, while monocytes were more sensitive to trametinib. Venetoclax exhibited dose dependent cell selectivity that inversely correlated to STAT3 phosphorylation. Lineage specific effect of midostaurin was similarly detected in CD19+/B cells from healthy, acute myeloid leukemia and chronic lymphocytic leukemia samples. Comparison of drug responses in healthy and neoplastic cells showed that healthy cell responses are predictive of the corresponding malignant cell response. Taken together, understanding drug sensitivity in the healthy cell-of-origin provides opportunities to obtain a new level of therapy precision and avoid off-target toxicity.
  • Zhong, Wenbin; Xu, Mengyang; Li, Chanjuan; Zhu, Biying; Cao, Xiuye; Li, Dan; Chen, Huanzhao; Hu, Chunxiu; Li, Rong; Luo, Chengwei; Pan, Guoping; Zhang, Wenqiang; Lai, Chaofeng; Wang, Tong; Du, Xin; Chen, Hong; Xu, Guowang; Olkkonen, Vesa M.; Lei, Pingsheng; Xu, Jun; Yan, Daoguang (2019)
    Leukemia stem cells (LSCs) are a rare subpopulation of abnormal hematopoietic stem cells (HSCs) that propagates leukemia and are responsible for the high frequency of relapse in therapies. Detailed insights into LSCs' survival will facilitate the identification of targets for therapeutic approaches. Here, we develop an inhibitor, LYZ-81, which targets ORP4L with high affinity and specificity and selectively eradicates LCSs in vitro and in vivo. ORP4L is expressed in LSCs but not in normal HSCs and is essential for LSC bioenergetics and survival. It extracts PIP2 from the plasma membrane and presents it to PLC beta 3, enabling IP3 generation and subsequentCa(2+)-dependent bioenergetics. LYZ-81 binds ORP4L competitively with PIP2 and blocks PIP2 hydrolysis, resulting in defective Ca2+ signaling. The results provide evidence that LSCs can be eradicated through the inhibition of ORP4L by LYZ-81, which may serve as a starting point of drug development for the elimination of LSCs to eventually cure leukemia.