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.
  • 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)
  • 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.
  • 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.
  • 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.
  • Yadav, Bhagwan; Pemovska, Tea; Szwajda, Agnieszka; Kulesskiy, Evgeny; Kontro, Mika; Karjalainen, Riikka; Majumder, Muntasir Mamun; Malani, Disha; Murumagi, Astrid; Knowles, Jonathan; Porkka, Kimmo; Heckman, Caroline; Kallioniemi, Olli; Wennerberg, Krister; Aittokallio, Tero (2014)
  • Klevebring, Daniel; Rosin, Gustaf; Ma, Ran; Lindberg, Johan; Czene, Kamila; Kere, Juha; Fredriksson, Irma; Bergh, Jonas; Hartman, Johan (2014)
  • Piazza, Rocco; Magistroni, Vera; Redaelli, Sara; Mauri, Mario; Massimino, Luca; Sessa, Alessandro; Peronaci, Marco; Lalowski, Maciej; Soliymani, Rabah; Mezzatesta, Caterina; Pirola, Alessandra; Banfi, Federica; Rubio, Alicia; Rea, Delphine; Stagno, Fabio; Usala, Emilio; Martino, Bruno; Campiotti, Leonardo; Merli, Michele; Passamonti, Francesco; Onida, Francesco; Morotti, Alessandro; Pavesi, Francesca; Bregni, Marco; Broccoli, Vania; Baumann, Marc; Gambacorti-Passerini, Carlo (2018)
    SETBP1 variants occur as somatic mutations in several hematological malignancies such as atypical chronic myeloid leukemia and as de novo germline mutations in the Schinzel-Giedion syndrome. Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Deletion of two AT-hooks abrogates the binding of SETBP1 to gDNA and impairs target gene upregulation. Genes controlled by SETBP1 such as MECOM are significantly upregulated in leukemias containing SETBP1 mutations. Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis. In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration. In summary, this work unveils a SETBP1 function that directly affects gene transcription and clarifies the mechanism operating in myeloid malignancies and in the Schinzel- Giedion syndrome caused by SETBP1 mutations.
  • Kumar, Ashwini; Kankainen, Matti; Parsons, Alun; Kallioniemi, Olli; Mattila, Pirkko; Heckman, Caroline A. (2017)
    Background: RNA sequencing (RNA-seq) has become an indispensable tool to identify disease associated transcriptional profiles and determine the molecular underpinnings of diseases. However, the broad adaptation of the methodology into the clinic is still hampered by inconsistent results from different RNA-seq protocols and involves further evaluation of its analytical reliability using patient samples. Here, we applied two commonly used RNA-seq library preparation protocols to samples from acute leukemia patients to understand how poly-A-tailed mRNA selection (PA) and ribo-depletion (RD) based RNA-seq library preparation protocols affect gene fusion detection, variant calling, and gene expression profiling. Results: Overall, the protocols produced similar results with consistent outcomes. Nevertheless, the PA protocol was more efficient in quantifying expression of leukemia marker genes and showed better performance in the expression-based classification of leukemia. Independent qRT-PCR experiments verified that the PA protocol better represented total RNA compared to the RD protocol. In contrast, the RD protocol detected a higher number of non-coding RNA features and had better alignment efficiency. The RD protocol also recovered more known fusion-gene events, although variability was seen in fusion gene predictions. Conclusion: The overall findings provide a framework for the use of RNA-seq in a precision medicine setting with limited number of samples and suggest that selection of the library preparation protocol should be based on the objectives of the analysis.