Publications by authors named "Jan-Henning Klusmann"

57 Publications

The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis.

Blood 2021 Sep 27. Epub 2021 Sep 27.

Martin-Luther-University Halle-Wittenberg, Germany.

Given the plasticity of hematopoietic stem/progenitor cells, multiple routes of differentiation must be blocked during acute myeloid leukemia pathogenesis - the molecular basis of which is incompletely understood. Here we report that post-transcriptional repression of the transcription factor ARID3A by miR-125b is a key event in megakaryoblastic leukemia (AMKL) pathogenesis. AMKL is frequently associated with trisomy 21 and GATA1 mutations (GATA1s), and children with Down syndrome are at a high risk of developing this disease. We show that chromosome 21-encoded miR-125b synergizes with Gata1s to drive leukemogenesis in this context. Leveraging forward and reverse genetics, we uncover Arid3a as the main miR-125b target behind this synergy. We demonstrate that, during normal hematopoiesis, this transcription factor promotes megakaryocytic differentiation in concert with GATA1 and mediates TGFβ-induced apoptosis and cell cycle arrest in complex with SMAD2/3. While Gata1s mutations perturb erythroid differentiation and induce hyperproliferation of megakaryocytic progenitors, intact ARID3A expression assures their megakaryocytic differentiation and growth restriction. Upon knockdown, these tumor suppressive functions are revoked, causing a dual megakaryocytic/erythroid differentiation blockade and subsequently AMKL. Inversely, restoring ARID3A expression relieves the megakaryocytic differentiation arrest in AMKL patient-derived xenografts. This work illustrates how mutations in lineage-determining transcription factors and perturbation of post-transcriptional gene regulation can interplay to block multiple routes of hematopoietic differentiation and cause leukemia. In AMKL, surmounting this differentiation blockade through restoration of the tumor suppressor ARID3A represents a promising strategy for treating this lethal pediatric disease.
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http://dx.doi.org/10.1182/blood.2021012231DOI Listing
September 2021

Recommendations for Diagnosis and Treatment of Children with Transient Abnormal Myelopoiesis (TAM) and Myeloid Leukemia in Down Syndrome (ML-DS).

Klin Padiatr 2021 Nov 18;233(6):267-277. Epub 2021 Aug 18.

Clinic for Pediatrics, University Hospital Frankfurt, Frankfurt, Germany.

Children with Down syndrome are at a high risk of developing transient abnormal myelopoiesis (TAM; synonym: TMD) or myeloid leukemia (ML-DS). While most patients with TAM are asymptomatic and go into spontaneous remission without a need for therapy, around 20% of patients die within the first six months due to TAM-related complications. Another 20-30% of patients progress from TAM to ML-DS. ML-DS patients are particularly vulnerable to therapy-associated toxicity, but the prognosis of relapsed ML-DS is extremely poor - thus, ML-DS therapy schemata must strive for a balance between appropriate efficacy (to avoid relapses) and treatment-related toxicity. This guideline presents diagnostic and therapeutic strategies for TAM and ML-DS based on the experience and results of previous clinical studies from the BFM working group, which have helped reduce the risk of early death in symptomatic TAM patients using low-dose cytarabine, and which have achieved excellent cure rates for ML-DS using intensity-reduced treatment protocols.
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http://dx.doi.org/10.1055/a-1532-2016DOI Listing
November 2021

The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets.

Cancer Discov 2021 Nov 9;11(11):2764-2779. Epub 2021 Aug 9.

Department of Pediatric Oncology and Hematology, University Hospital Magdeburg, Magdeburg, Germany.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99-not applicable], compared with 117 days (95% CI, 106-143; = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. SIGNIFICANCE: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes...
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http://dx.doi.org/10.1158/2159-8290.CD-21-0094DOI Listing
November 2021

Survival Following Relapse in Children with Acute Myeloid Leukemia: A Report from AML-BFM and COG.

Cancers (Basel) 2021 May 12;13(10). Epub 2021 May 12.

Department of Pediatric Hematology-Oncology, Pediatrics III, University Hospital of Essen, 45147 Essen, Germany.

Post-relapse therapy remains critical for survival in children with acute myeloid leukemia (AML). We evaluated survival, response and prognostic variables following relapse in independent cooperative group studies conducted by COG and the population-based AML-BFM study group. BFM included 197 patients who relapsed after closure of the last I-BFM relapse trial until 2017, while COG included 852 patients who relapsed on the last Phase 3 trials (AAML0531, AAML1031). Overall survival at 5 years (OS) was 42 ± 4% (BFM) and 35 ± 2% (COG). Initial high-risk features (BFM 32 ± 6%, COG 26 ± 4%) and short time to relapse (BFM 29 ± 4%, COG 25 ± 2%) predicted diminished survival. In the BFM dataset, there was no difference in OS for patients who had a complete remission with full hematopoietic recovery (CR) following post-relapse re-induction compared to those with partial neutrophil and platelet recovery (CRp and CRi) only (52 ± 7% vs. 63 ± 10%, = 0.39). Among 90 patients alive at last follow-up, 87 had received a post-relapse hematopoietic stem cell transplant (HSCT). OS for patients with post-relapse HSCT was 54 ± 4%. In conclusion, initial high-risk features and early relapse remain prognostic. Response assessment with full hematopoietic recovery following initial relapse therapy does not predict survival. These data indicate the need for post-relapse risk stratification in future studies of relapse therapies.
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http://dx.doi.org/10.3390/cancers13102336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151466PMC
May 2021

Molecular Mechanisms of the Genetic Predisposition to Acute Megakaryoblastic Leukemia in Infants With Down Syndrome.

Front Oncol 2021 11;11:636633. Epub 2021 Mar 11.

Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.

Individuals with Down syndrome are genetically predisposed to developing acute megakaryoblastic leukemia. This myeloid leukemia associated with Down syndrome (ML-DS) demonstrates a model of step-wise leukemogenesis with perturbed hematopoiesis already presenting , facilitating the acquisition of additional driver mutations such as truncating variants, which are pathognomonic to the disease. Consequently, the affected individuals suffer from a transient abnormal myelopoiesis (TAM)-a pre-leukemic state preceding the progression to ML-DS. In our review, we focus on the molecular mechanisms of the different steps of clonal evolution in Down syndrome leukemogenesis, and aim to provide a comprehensive view on the complex interplay between gene dosage imbalances, mutations and somatic mutations affecting JAK-STAT signaling, the cohesin complex and epigenetic regulators.
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http://dx.doi.org/10.3389/fonc.2021.636633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992977PMC
March 2021

Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Eur J Cancer 2020 09 17;136:116-129. Epub 2020 Jul 17.

FORMA Therapeutics, USA.

Purpose: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives.

Methods: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents.

Results: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field.

Conclusion: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.
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http://dx.doi.org/10.1016/j.ejca.2020.04.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789799PMC
September 2020

YBX1 Indirectly Targets Heterochromatin-Repressed Inflammatory Response-Related Apoptosis Genes through Regulating CBX5 mRNA.

Int J Mol Sci 2020 Jun 23;21(12). Epub 2020 Jun 23.

Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.

Medulloblastomas arise from undifferentiated precursor cells in the cerebellum and account for about 20% of all solid brain tumors during childhood; standard therapies include radiation and chemotherapy, which oftentimes come with severe impairment of the cognitive development of the young patients. Here, we show that the posttranscriptional regulator Y-box binding protein 1 (YBX1), a DNA- and RNA-binding protein, acts as an oncogene in medulloblastomas by regulating cellular survival and apoptosis. We observed different cellular responses upon YBX1 knockdown in several medulloblastoma cell lines, with significantly altered transcription and subsequent apoptosis rates. Mechanistically, PAR-CLIP for YBX1 and integration with RNA-Seq data uncovered direct posttranscriptional control of the heterochromatin-associated gene ; upon YBX1 knockdown and subsequent CBX5 mRNA instability, heterochromatin-regulated genes involved in inflammatory response, apoptosis and death receptor signaling were de-repressed. Thus, YBX1 acts as an oncogene in medulloblastoma through indirect transcriptional regulation of inflammatory genes regulating apoptosis and represents a promising novel therapeutic target in this tumor entity.
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http://dx.doi.org/10.3390/ijms21124453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352269PMC
June 2020

Childhood Obesity and Cancer Risk in Adulthood.

Curr Obes Rep 2020 Sep;9(3):204-212

Clinic for Pediatrics I, University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany.

Purpose Of Review: The purpose of this review is to summarize our current understanding of the association between childhood obesity and cancer risk later in life.

Recent Findings: Adipose tissue secrets a variety of adipocytokines, and expression and/or secretion rate of most of them seems to be increased or dysregulated in obesity. In addition, obesity leads to increased secretion of proinflammatory cytokines such as interferon-γ (IFN-γ), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α), which promotes an infiltration of inflammatory immune cells into adipose tissue. This process may facilitate a state of "subclinical inflammation" (metaflammation) and may lead to the development of the metabolic syndrome (MetS), starting as early as during childhood. In addition, several oncogenes have been linked to inflammation and cancer development via different pathways, and several types of tumors need an inflammatory environment before a malignant change occurs. An inflammatory environment seems to promote the proliferation and survival of malignant cells as well as angiogenesis. Natural killer (NK) cells play an important role in this process, as they are able to kill transformed cells without prior sensitization and coordinate subsequent immune responses by producing distinct cytokines, thus providing antitumor immunity. First studies in children have suggested that NK cells from obese children are activated, metabolically stressed, and functionally deficient. This may lead to a suppression of antitumor immunity as early as during childhood, probably many years before the development of cancer. Epidemiological studies have shown a strong association between higher body mass index (BMI) during childhood and adolescence and increased risk for several malignancies in adulthood, including leukemia, Hodgkin's disease, colorectal cancer, and breast cancer. Underlying mechanisms are not completely understood, but several adipocytokines and inflammatory markers including NK cells seem to be "key players" in this process.
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http://dx.doi.org/10.1007/s13679-020-00387-wDOI Listing
September 2020

RNA-Binding Proteins in Acute Leukemias.

Int J Mol Sci 2020 May 12;21(10). Epub 2020 May 12.

Department of Pediatrics 1, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany.

Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions.
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http://dx.doi.org/10.3390/ijms21103409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279408PMC
May 2020

Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome.

Eur J Immunol 2020 07 20;50(7):1078-1080. Epub 2020 Apr 20.

Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.

AMPK (adenosine monophosphate-activated protein kinase) is phosphorylated (AMPK-P) in response to low energy through allosteric activation by Adenosine mono- or diphosphate (AMP/ADP). Folliculin (FLCN) and the FLCN-interacting proteins 1 and 2 (FNIP1, 2) modulate AMPK. FNIP1 deficiency patients have a AMPK-P gain of function phenotype with hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome, myopathy of skeletal muscles and combined immunodeficiency.
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http://dx.doi.org/10.1002/eji.201948504DOI Listing
July 2020

The stem cell-specific long noncoding RNA HOXA10-AS in the pathogenesis of KMT2A-rearranged leukemia.

Blood Adv 2019 12;3(24):4252-4263

Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.

HOX genes are highly conserved, and their precisely controlled expression is crucial for normal hematopoiesis. Accordingly, deregulation of HOX genes can cause leukemia. However, despite of intensive research on the coding HOX genes, the role of the numerous long noncoding RNAs (lncRNAs) within the HOX clusters during hematopoiesis and their contribution to leukemogenesis are incompletely understood. Here, we show that the lncRNA HOXA10-AS, located antisense to HOXA10 and mir-196b in the HOXA cluster, is highly expressed in hematopoietic stem cells (HSCs) as well as in KMT2A-rearranged and NPM1 mutated acute myeloid leukemias (AMLs). Using short hairpin RNA- and locked nucleic acid-conjugated chimeric antisense oligonucleotide (LNA-GapmeR)-mediated HOXA10-AS-knockdown and CRISPR/Cas9-mediated excision in vitro, we demonstrate that HOXA10-AS acts as an oncogene in KMT2A-rearranged AML. Moreover, HOXA10-AS knockdown severely impairs the leukemic growth of KMT2A-rearranged patient-derived xenografts in vivo, while high HOXA10-AS expression can serve as a marker of poor prognosis in AML patients. Lentiviral expression of HOXA10-AS blocks normal monocytic differentiation of human CD34+ hematopoietic stem and progenitor cells. Mechanistically, we show that HOXA10-AS localizes in the cytoplasm and acts in trans to induce NF-κB target genes. In total, our data imply that the normally HSC-specific HOXA10-AS is an oncogenic lncRNA in KMT2A-r AML. Thus, it may also represent a potential therapeutic target in KMT2A-rearranged AML.
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http://dx.doi.org/10.1182/bloodadvances.2019032029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929382PMC
December 2019

Musashi1 enhances chemotherapy resistance of pediatric glioblastoma cells in vitro.

Pediatr Res 2020 03 22;87(4):669-676. Epub 2019 Nov 22.

Department of Pediatric Hematology/Oncology, University Hospital, Halle (Saale), Germany.

Background: Glioblastoma (GBM) is the most aggressive form of glioma in adults and children and is associated with very poor prognosis. Pediatric tumors are biologically distinct from adult GBM and differ in response to current GBM treatment protocols. Regarding pediatric GBM, new drug combinations and the molecular background of chemotherapy effects need to be investigated, in order to increase patient survival outcome.

Methods: The expression of the RNA-binding protein Musashi1 (MSI1) in pediatric glioma samples of different WHO tumor grades was investigated on the protein (immunohistochemistry) and on the RNA level (publicly accessible RNA sequencing dataset). The impact of the chemotherapeutic temozolomide (TMZ) in combination with valproic acid (VPA) was tested in two pediatric glioblastoma-derived cell lines. The supportive effect of MSI1 expression against this treatment was investigated via transient knockdown and protein overexpression.

Results: MSI1 expression correlates with pediatric high-grade glioma (HGG). The combination of TMZ with VPA significantly increases the impact of drug treatment on cell viability in vitro. MSI1 was found to promote drug resistance to the combined treatment with TMZ and VPA.

Conclusion: MSI1 expression is a potential marker for pediatric HGG and increases chemoresistance. Inhibition of MSI1 might lead to an improved patient outcome and therapy response.
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http://dx.doi.org/10.1038/s41390-019-0628-9DOI Listing
March 2020

Molecular Approaches to Treating Pediatric Leukemias.

Front Pediatr 2019 6;7:368. Epub 2019 Sep 6.

Department of Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.

Over the past decades, striking progress has been made in the treatment of pediatric leukemia, approaching 90% overall survival in children with acute lymphoblastic leukemia (ALL) and 75% in children with acute myeloid leukemia (AML). This has mainly been achieved through multiagent chemotherapy including CNS prophylaxis and risk-adapted therapy within collaborative clinical trials. However, prognosis in children with refractory or relapsed leukemia remains poor and has not significantly improved despite great efforts. Hence, more effective and less toxic therapies are urgently needed. Our understanding of disease biology, molecular drivers, drug resistance and, thus, the possibility to identify children at high-risk for treatment failure has significantly improved in recent years. Moreover, several new drugs targeting key molecular pathways involved in leukemia development, cell growth, and proliferation have been developed and approved. These striking achievements are linked to the great hope to further improve survival in children with refractory and relapsed leukemia. This review gives an overview on current molecularly targeted therapies in children with leukemia, including kinase, and proteasome inhibitors, epigenetic and enzyme targeting, as well as apoptosis regulators among others.
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http://dx.doi.org/10.3389/fped.2019.00368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742719PMC
September 2019

The Regulatory Roles of Long Noncoding RNAs in Acute Myeloid Leukemia.

Front Oncol 2019 9;9:570. Epub 2019 Jul 9.

Department of Pediatrics I, Martin Luther University Halle-Wittenberg, Halle, Germany.

In this post-genomic era, long noncoding RNAs (lncRNAs) are rapidly gaining recognition for their crucial roles across diverse biological processes and contexts. The human blood system is no exception, where dozens of lncRNAs have been established as regulators of normal and/or malignant hematopoiesis, and where ongoing works continue to uncover novel lncRNA functions. Our review focuses on lncRNAs that are involved in the pathogenesis of acute myeloid leukemia (AML) and the mechanisms through which they control gene expression in this disease context. We also comment on genome-wide sequencing or profiling studies that have implicated large sets of lncRNAs in AML pathophysiology.
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http://dx.doi.org/10.3389/fonc.2019.00570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629768PMC
July 2019

Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.

Cancer Cell 2019 08 11;36(2):123-138.e10. Epub 2019 Jul 11.

MRC MHU, BRC Hematology Theme, Oxford Biomedical Research Centre, Oxford Centre for Haematology, WIMM, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; Department of Paediatrics, University of Oxford, Oxford OX3 9DS, UK.

Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.
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http://dx.doi.org/10.1016/j.ccell.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863161PMC
August 2019

Biology-Driven Approaches to Prevent and Treat Relapse of Myeloid Neoplasia after Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 04 15;25(4):e128-e140. Epub 2019 Jan 15.

Department of Internal Medicine IV, Hematology and Oncology, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle, Germany.

The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.016DOI Listing
April 2019

Childhood obesity: increased risk for cardiometabolic disease and cancer in adulthood.

Metabolism 2019 03 5;92:147-152. Epub 2018 Dec 5.

Department of Pediatrics I, Martin-Luther-University Halle-Wittenberg, Halle, Germany.

Prevalence of childhood obesity has worldwide more than doubled since 1980. Underlying factors are complex and are far from completely understood. Strategies to prevent childhood obesity have mainly focused on behavioral intervention; and obesity therapy was mainly based on lifestyle modification to date. However, effects for both have been quite limited so far and no country has succeeded in fighting the obesity epidemy we are facing. Normalization of body weight before onset of puberty is crucial for several reasons: First, obese children and adolescents frequently stay obese until adulthood. Second, obesity during adolescence is significantly associated with increased risk for cardiovascular and metabolic disease such as type 2 diabetes in adulthood. And third, recent data have shown a strong association between higher body mass index (BMI) during adolescence and increased risk for several malignancies such as leukemia, Hodgkin's disease, colorectal cancer, breast cancer and others in adulthood. This review summarizes our current understanding of epidemiology, underlying factors, concomitant disease, as well as available intervention strategies and gives an overview of what has been reached so far and what measures should be undertaken to counteract the obesogenic environment.
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http://dx.doi.org/10.1016/j.metabol.2018.12.001DOI Listing
March 2019

Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study.

Blood Adv 2018 07;2(13):1532-1540

Department of Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.

Approximately 5% to 10% of children with Down syndrome (DS) are diagnosed with transient myeloproliferative disorder (TMD). Approximately 20% of these patients die within 6 months (early death), and another 20% to 30% progress to myeloid leukemia (ML-DS) within their first 4 years of life. The aim of the multicenter, nonrandomized, historically controlled TMD Prevention 2007 trial was to evaluate the impact of low-dose cytarabine treatment on survival and prevention of ML-DS in patients with TMD. Patients received cytarabine (1.5 mg/kg for 7 days) in case of TMD-related symptoms at diagnosis (high white blood cell count, ascites, liver dysfunction, hydrops fetalis) or detection of minimal residual disease (MRD) 8 weeks after diagnosis. The 5-year probability of event-free and overall survival of 102 enrolled TMD patients was 72 ± 5% and 91 ± 3%, respectively. In patients eligible for treatment because of symptoms (n = 43), we observed a significantly lower cumulative incidence (CI) of early death as compared with symptomatic patients in the historical control (n = 45) (12 ± 5% vs 33 ± 7%, = .02). None of the asymptomatic patients in the current study suffered early death. However, the treatment of symptomatic or MRD-positive patients did not result in a significantly lower CI of ML-DS (25 ± 7% [treated] vs 14 ± 7% [untreated], = .34 [per protocol analysis]; historical control: 22 ± 4%, = .55). Thus, low-dose cytarabine treatment helped to reduce TMD-related mortality when compared with the historical control but was insufficient to prevent progression to ML-DS. This trial was registered at EudraCT as #2006-002962-20.
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http://dx.doi.org/10.1182/bloodadvances.2018018945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039662PMC
July 2018

s exerts developmental stage-specific effects in human hematopoiesis.

Haematologica 2018 08 22;103(8):e336-e340. Epub 2018 Mar 22.

Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle, Germany

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http://dx.doi.org/10.3324/haematol.2018.191338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068023PMC
August 2018

Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012.

Leukemia 2018 10 22;32(10):2167-2177. Epub 2018 Feb 22.

Department of Pediatric Hematology-Oncology, Pediatrics III, University Hospital of Essen, Essen, Germany.

Overall survival (OS) of pediatric patients with acute myeloid leukemia (AML) increased in recent decades. However, it remained unknown whether advances in first-line treatment, supportive care, or second-line therapy mainly contributed to this improvement. Here, we retrospectively analyzed outcome and clinical data of 1940 pediatric AML patients (younger than 18 years of age), enrolled in the population-based AML-BFM trials between 1987 and 2012. While 5-year probability of OS (pOS) increased from 49 ± 3% (1987-1992) to 76 ± 4% (2010-2012; p < 0.0001), probability of event-free survival only improved from 41 ± 3% (1987-1992) to 50 ± 2% (1993-1998; p = 0.02) after introduction of high-dose cytarabine/mitoxantrone, but remained stable since then. Non-response and relapse rates stayed constant despite intensified first-line therapy (p = 0.08 and p = 0.17). Reduced fatal bleedings and leukostasis translated into fewer early deaths (8.1%vs. 2.2%; p = 0.001). Strikingly, pOS after non-response (13 ± 5% (1987-1992) vs. 43 ± 7% (2005-2010); p < 0.0001) or relapse (19 ± 4% vs. 45 ± 4%; p < 0.0001) improved. After 1999, more relapsed or refractory patients underwent hematopoietic stem cell transplantation (HSCT) with increased pOS after HSCT (29 ± 5% (1993-1998) vs. 50 ± 4% (2005-2010); p < 0.0001). Since efficacy of salvage therapy mainly contributed to better outcome in pediatric AML, our analysis indicates that a better allocation of patients, who cannot be cured with conventional chemotherapy, to an early "salvage-like" therapy is necessary.
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http://dx.doi.org/10.1038/s41375-018-0071-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170392PMC
October 2018

Endogenous Tumor Suppressor microRNA-193b: Therapeutic and Prognostic Value in Acute Myeloid Leukemia.

J Clin Oncol 2018 04 12;36(10):1007-1016. Epub 2018 Feb 12.

Raj Bhayadia, Razan Jammal, Stephan Emmrich, Jan Fiedler, Adrian Schwarzer, Michael Heuser, Michelle Ng, Dirk Heckl, and Thomas Thum, Hannover Medical School, Hannover; Raj Bhayadia, Michelle Ng, and Jan-Henning Klusmann, University of Halle, Halle; Kathrin Krowiorz, Arefeh Rouhi, Konstanze Döhner, Hartmut Döhner, and Florian Kuchenbauer, University Hospital of Ulm, Ulm; Nadine Haetscher, Susanne Wingert, Sabrina Bothur, and Michael A. Rieger, Goethe University Frankfurt, Frankfurt; Sabrina Bothur and Michael A. Rieger, German Cancer Consortium, and German Cancer Research Center, Heidelberg; Dirk Reinhardt, University Hospital Essen, Essen, Germany; Askar Obulkasim, C. Michel Zwaan, and Maarten Fornerod, Erasmus MC/Sophia Children's Hospital, Rotterdam; Marry van den Heuvel Eibrink, Prinses Maxima Center for Pediatric Oncology, Utrecht, the Netherlands; Tobias Mätzig and R. Keith Humphries, Terry Fox Laboratory, Vancouver, Canada; and Thomas Thum, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo. Results miR-193b exerted important, endogenous, tumor-suppressive functions on the hematopoietic system. miR-193b-3p was downregulated in several cytogenetically defined subgroups of pediatric and adult AML, and low expression served as an independent indicator for poor prognosis in pediatric AML (risk ratio ± standard error, -0.56 ± 0.23; P = .016). miR-193b-3p expression improved the prognostic value of the European LeukemiaNet risk-group stratification or a 17-gene leukemic stemness score. In knockout mice, loss of miR-193b cooperated with Hoxa9/Meis1 during leukemogenesis, whereas restoring miR-193b expression impaired leukemic engraftment. Similarly, expression of miR-193b in AML blasts from patients diminished leukemic growth in vitro and in mouse xenografts. Mechanistically, miR-193b induced apoptosis and a G1/S-phase block in various human AML subgroups by targeting multiple factors of the KIT-RAS-RAF-MEK-ERK (MAPK) signaling cascade and the downstream cell cycle regulator CCND1. Conclusion The tumor-suppressive function is independent of patient age or genetics; therefore, restoring miR-193b would assure high antileukemic efficacy by blocking the entire MAPK signaling cascade while preventing the emergence of resistance mechanisms.
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http://dx.doi.org/10.1200/JCO.2017.75.2204DOI Listing
April 2018

Gene correction of reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells.

Blood Adv 2017 Jun 2;1(14):903-914. Epub 2017 Jun 2.

Department of Pediatric Hematology and Oncology.

Severe congenital neutropenia (SCN, Kostmann disease) is a heritable disorder characterized by a granulocytic maturation arrest. Biallelic mutations in () are frequently detected in affected individuals, including those of the original pedigree described by Kostmann in 1956. To date, no faithful animal model has been established to study SCN mediated by HAX1 deficiency. Here we demonstrate defective neutrophilic differentiation and compensatory monocyte overproduction from patient-derived induced pluripotent stem cells (iPSCs) carrying the homozygous nonsense mutation. Targeted correction of the mutation using the CRISPR-Cas9 system and homologous recombination rescued neutrophil differentiation and reestablished an and -centered transcription network in immature myeloid progenitors, which is involved in the regulation of apoptosis, apoptotic mitochondrial changes, and myeloid differentiation. These findings made in isogenic iPSC-derived myeloid cells highlight the complex transcriptional changes underlying Kostmann disease. Thus, we show that patient-derived -iPSCs recapitulate the Kostmann disease phenotype in vitro and confirm mutations as the disease-causing monogenic lesion. Finally, our study paves the way for nonvirus-based gene therapy approaches in SCN.
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http://dx.doi.org/10.1182/bloodadvances.2016003798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737589PMC
June 2017

Refined sgRNA efficacy prediction improves large- and small-scale CRISPR-Cas9 applications.

Nucleic Acids Res 2018 02;46(3):1375-1385

Pediatric Hematology & Oncology, Hannover Medical School, Hannover, Germany.

Genome editing with the CRISPR-Cas9 system has enabled unprecedented efficacy for reverse genetics and gene correction approaches. While off-target effects have been successfully tackled, the effort to eliminate variability in sgRNA efficacies-which affect experimental sensitivity-is in its infancy. To address this issue, studies have analyzed the molecular features of highly active sgRNAs, but independent cross-validation is lacking. Utilizing fluorescent reporter knock-out assays with verification at selected endogenous loci, we experimentally quantified the target efficacies of 430 sgRNAs. Based on this dataset we tested the predictive value of five recently-established prediction algorithms. Our analysis revealed a moderate correlation (r = 0.04 to r = 0.20) between the predicted and measured activity of the sgRNAs, and modest concordance between the different algorithms. We uncovered a strong PAM-distal GC-content-dependent activity, which enabled the exclusion of inactive sgRNAs. By deriving nine additional predictive features we generated a linear model-based discrete system for the efficient selection (r = 0.4) of effective sgRNAs (CRISPRater). We proved our algorithms' efficacy on small and large external datasets, and provide a versatile combined on- and off-target sgRNA scanning platform. Altogether, our study highlights current issues and efforts in sgRNA efficacy prediction, and provides an easily-applicable discrete system for selecting efficient sgRNAs.
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http://dx.doi.org/10.1093/nar/gkx1268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814880PMC
February 2018

lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling.

Nat Med 2017 Nov 16;23(11):1331-1341. Epub 2017 Oct 16.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

De novo and acquired resistance, which are largely attributed to genetic alterations, are barriers to effective anti-epidermal-growth-factor-receptor (EGFR) therapy. To generate cetuximab-resistant cells, we exposed cetuximab-sensitive colorectal cancer cells to cetuximab in three-dimensional culture. Using whole-exome sequencing and transcriptional profiling, we found that the long non-coding RNA MIR100HG and two embedded microRNAs, miR-100 and miR-125b, were overexpressed in the absence of known genetic events linked to cetuximab resistance. MIR100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/β-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness. Our results describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR-125b targeting of GATA6. These findings identify a clinically actionable, epigenetic cause of cetuximab resistance.
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http://dx.doi.org/10.1038/nm.4424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961502PMC
November 2017

The non-coding RNA landscape of human hematopoiesis and leukemia.

Nat Commun 2017 08 9;8(1):218. Epub 2017 Aug 9.

Pediatric Hematology and Oncology, Hannover Medical School, Hannover, 30625, Germany.

Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions. However, their expression patterns and regulatory functions during normal and malignant human hematopoiesis are incompletely understood. Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system. Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-and assign these to critical regulatory circuits involved in blood homeostasis. Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells. Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.While micro-RNAs are known regulators of haematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear. Here the authors provide a non-coding RNA expression landscape of the human hematopoietic system, highlighting their role in the formation and maintenance of the human blood hierarchy.
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http://dx.doi.org/10.1038/s41467-017-00212-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550424PMC
August 2017

CRISPR-Cas9-induced t(11;19)/MLL-ENL translocations initiate leukemia in human hematopoietic progenitor cells .

Haematologica 2017 09 1;102(9):1558-1566. Epub 2017 Jun 1.

Pediatric Hematology & Oncology, Hannover Medical School, Germany

Chromosomal translocations that generate oncogenic fusion proteins are causative for most pediatric leukemias and frequently affect the gene. modeling of chromosomal translocations in human hematopoietic stem and progenitor cells is challenging but essential to determine their actual leukemogenic potential. We therefore developed an advanced lentiviral CRISPR-Cas9 vector that efficiently transduced human CD34 hematopoietic stem and progenitor cells and induced the t(11;19)/MLL-ENL translocation. Leveraging this system, we could demonstrate that hematopoietic stem and progenitor cells harboring the translocation showed only a transient clonal growth advantage In contrast, t(11;19)/MLL-ENL-harboring CD34 hematopoietic stem and progenitor cells not only showed long-term engraftment in primary immunodeficient recipients, but t(11;19)/MLL-ENL also served as a first hit to initiate a monocytic leukemia-like disease. Interestingly, secondary recipients developed acute lymphoblastic leukemia with incomplete penetrance. These findings indicate that environmental cues not only contribute to the disease phenotype, but also to t(11;19)/MLL-ENL-mediated oncogenic transformation itself. Thus, by investigating the true chromosomal t(11;19) rearrangement in its natural genomic context, our study emphasizes the importance of environmental cues for the pathogenesis of pediatric leukemias, opening an avenue for novel treatment options.
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http://dx.doi.org/10.3324/haematol.2017.164046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685230PMC
September 2017
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