Publications by authors named "Torsten Haferlach"

411 Publications

NOVEL NPM1 EXON 5 MUTATIONS AND GENE FUSIONS LEADING TO ABERRANT CYTOPLASMIC NUCLEOPHOSMIN IN AML.

Blood 2021 08 3. Epub 2021 Aug 3.

Munich Leukemia Laboratory, Munich, Germany.

Nucleophosmin (NPM1) mutations in acute myeloid leukemia (AML) affect exon 12, but sporadically also exon 9 and 11, all causing changes at protein C-terminal end (loss of tryptophans and creation of a nuclear export signal-NES motif) that lead to aberrant cytoplasmic NPM1 (NPM1c+), detectable by immunohistochemistry. Combining immunohistochemistry and molecular analyses in 929 AML patients, we found non-exon 12 NPM1 mutations in 5/387 (1.3%) NPM1c+ cases. Besides mutations in exon 9 (n=1) and exon 11 (n=1), novel mutations in exon 5 were discovered (n=3). One more exon 5 mutation was identified in additional 141 AML patients selected for wild-type NPM1 exon 12. Furthermore, 3 NPM1 rearrangements (i.e. NPM1/RPP30, NPM1/SETBP1, NPM1/CCDC28A) were detected and characterized among 13,979 AML samples screened by cytogenetic/FISH and RNA sequencing. Functional studies demonstrated that in AML cases the new NPM1 proteins harboured an efficient extra NES, either newly created or already present in the fusion partner, ensuring its cytoplasmic accumulation. Our findings support NPM1 cytoplasmic relocation as critical for leukemogenesis and reinforce the role of immunohistochemistry in predicting any AML-associated NPM1 genetic lesions. Also, this study highlights the need for developing new specific assays for molecular diagnosis and monitoring of NPM1-mutated AML.
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http://dx.doi.org/10.1182/blood.2021012732DOI Listing
August 2021

Clinical application of whole transcriptome sequencing for the classification of patients with acute lymphoblastic leukemia.

BMC Cancer 2021 Aug 2;21(1):886. Epub 2021 Aug 2.

MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, 81377, Munich, Germany.

Background: Considering the clinical and genetic characteristics, acute lymphoblastic leukemia (ALL) is a rather heterogeneous hematological neoplasm for which current standard diagnostics require various analyses encompassing morphology, immunophenotyping, cytogenetics, and molecular analysis of gene fusions and mutations. Hence, it would be desirable to rely on a technique and an analytical workflow that allows the simultaneous analysis and identification of all the genetic alterations in a single approach. Moreover, based on the results with standard methods, a significant amount of patients have no established abnormalities and hence, cannot further be stratified.

Methods: We performed WTS and WGS in 279 acute lymphoblastic leukemia (ALL) patients (B-cell: n = 211; T-cell: n = 68) to assess the accuracy of WTS, to detect relevant genetic markers, and to classify ALL patients.

Results: DNA and RNA-based genotyping was used to ensure correct WTS-WGS pairing. Gene expression analysis reliably assigned samples to the B Cell Precursor (BCP)-ALL or the T-ALL group. Subclassification of BCP-ALL samples was done progressively, assessing first the presence of chromosomal rearrangements by the means of fusion detection. Compared to the standard methods, 97% of the recurrent risk-stratifying fusions could be identified by WTS, assigning 76 samples to their respective entities. Additionally, read-through fusions (indicative of CDKN2A and RB1 gene deletions) were recurrently detected in the cohort along with 57 putative novel fusions, with yet untouched diagnostic potentials. Next, copy number variations were inferred from WTS data to identify relevant ploidy groups, classifying an additional of 31 samples. Lastly, gene expression profiling detected a BCR-ABL1-like signature in 27% of the remaining samples.

Conclusion: As a single assay, WTS allowed a precise genetic classification for the majority of BCP-ALL patients, and is superior to conventional methods in the cases which lack entity defining genetic abnormalities.
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http://dx.doi.org/10.1186/s12885-021-08635-5DOI Listing
August 2021

Clinical interpretation of whole-genome and whole-transcriptome sequencing for precision oncology.

Semin Cancer Biol 2021 Jul 10. Epub 2021 Jul 10.

Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, United States. Electronic address:

Whole-genome sequencing either alone or in combination with whole-transcriptome sequencing has started to be used to analyze clinical tumor samples to improve diagnosis, provide risk stratification, and select patient-specific therapies. Compared with current genomic testing strategies, largely focused on small number of genes tested individually or targeted panels, whole-genome and transcriptome sequencing (WGTS) provides novel opportunities to identify and report a potentially much larger number of actionable alterations with diagnostic, prognostic, and/or predictive impact. Such alterations include point mutations, indels, copy- number aberrations and structural variants, but also germline variants, fusion genes, noncoding alterations and mutational signatures. Nevertheless, these comprehensive tests are accompanied by many challenges ranging from the extent and diversity of sequence alterations detected by these methods to the complexity and limited existing standardization in interpreting them. We describe the challenges of WGTS interpretation and the opportunities with comprehensive genomic testing.
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http://dx.doi.org/10.1016/j.semcancer.2021.07.003DOI Listing
July 2021

Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.

Leukemia 2021 Jun 30. Epub 2021 Jun 30.

MLL Munich Leukemia Laboratory, Munich, Germany.

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.
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http://dx.doi.org/10.1038/s41375-021-01318-xDOI Listing
June 2021

Clinical utility of whole-genome sequencing in precision oncology.

Semin Cancer Biol 2021 Jun 25. Epub 2021 Jun 25.

NIHR Oxford Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, United Kingdom. Electronic address:

Precision diagnostics is one of the two pillars of precision medicine. Sequencing efforts in the past decade have firmly established cancer as a primarily genetically driven disease. This concept is supported by therapeutic successes aimed at particular pathways that are perturbed by specific driver mutations in protein-coding domains and reflected in three recent FDA tissue agnostic cancer drug approvals. In addition, there is increasing evidence from studies that interrogate the entire genome by whole-genome sequencing that acquired global and complex genomic aberrations including those in non-coding regions of the genome might also reflect clinical outcome. After addressing technical, logistical, financial and ethical challenges, national initiatives now aim to introduce clinical whole-genome sequencing into real-world diagnostics as a rational and potentially cost-effective tool for response prediction in cancer and to identify patients who would benefit most from 'expensive' targeted therapies and recruitment into clinical trials. However, so far, this has not been accompanied by a systematic and prospective evaluation of the clinical utility of whole-genome sequencing within clinical trials of uniformly treated patients of defined clinical outcome. This approach would also greatly facilitate novel predictive biomarker discovery and validation, ultimately reducing size and duration of clinical trials and cost of drug development. This manuscript is the third in a series of three to review and critically appraise the potential and challenges of clinical whole-genome sequencing in solid tumors and hematological malignancies.
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http://dx.doi.org/10.1016/j.semcancer.2021.06.018DOI Listing
June 2021

Genome Sequencing in Myeloid Cancers.

N Engl J Med 2021 Jun;384(25):e106

Munich Leukemia Laboratory, Munich, Germany

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http://dx.doi.org/10.1056/NEJMc2106014DOI Listing
June 2021

Adverse prognostic impact of complex karyotype (≥3 cytogenetic alterations) in adult T-cell acute lymphoblastic leukemia (T-ALL).

Leuk Res 2021 Jun 8;109:106612. Epub 2021 Jun 8.

Centro de Investigación del Cáncer (IBMCC-CSIC/USAL) (CIC), Hospital Clínico Universitario de Salamanca (HUS), Instituto Bio-Sanitario de Salamanca (IBSAL), CIBERONC, Salamanca, Spain.

The potential prognostic value of conventional karyotyping in adult T-cell acute lymphoblastic leukemia (T-ALL) remains an open question. We hypothesized that a modified cytogenetic classification, based on the number and type of cytogenetic abnormalities, would allow the identification of high-risk adult T-ALL patients. Complex karyotype defined by the presence of ≥3 cytogenetic alterations identified T-ALL patients with poor prognosis in this study. Karyotypes with ≥3 abnormalities accounted for 16 % (22/139) of all evaluable karyotypes, corresponding to the largest poor prognosis cytogenetic subgroup of T-ALL identified so far. Patients carrying karyotypes with ≥3 cytogenetic alterations showed a significantly inferior response to therapy, and a poor outcome in terms of event-free survival (EFS), overall survival (OS) and cumulative incidence of relapse (CIR), independently of other baseline characteristics and the end-induction minimal residual disease (MRD) level. Additional molecular analyses of patients carrying ≥3 cytogenetic alterations showed a unique molecular profile that could contribute to understand the underlying molecular mechanisms of resistance and to evaluate novel targeted therapies (e.g. IL7R directed) with potential impact on outcome of adult T-ALL patients.
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http://dx.doi.org/10.1016/j.leukres.2021.106612DOI Listing
June 2021

Clinical relevance of clonal hematopoiesis in the oldest-old population.

Blood 2021 Jun 14. Epub 2021 Jun 14.

IRCCS Humanitas Clinical Institute, Rozzano, Italy.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies and investigate the relationships between CHIP and associated pathologies. Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions) and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was a common finding in oldest-old population, the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. In conclusion, specific mutational patterns define different risk of developing myeloid neoplasms vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.
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http://dx.doi.org/10.1182/blood.2021011320DOI Listing
June 2021

Analytical demands to use whole-genome sequencing in precision oncology.

Semin Cancer Biol 2021 Jun 10. Epub 2021 Jun 10.

MLL Munich Leukemia Laboratory, Munich, Germany. Electronic address:

Interrogating the tumor genome in its entirety by whole-genome sequencing (WGS) offers an unprecedented insight into the biology and pathogenesis of cancer, with potential impact on diagnostics, prognostication and therapy selection. WGS is able to detect sequence as well as structural variants and thereby combines central domains of cytogenetics and molecular genetics. Given the potential of WGS in directing targeted therapeutics and clinical decision-making, we envision a gradual transition of the method from research to clinical routine. This review is one out of three within this issue aimed at facilitating this effort, by discussing in-depth analytical validation, clinical interpretation and clinical utility of WGS. The review highlights the requirements for implementing, validating and maintaining a clinical WGS pipeline to obtain high-quality patient-specific data in accordance with the local regulatory landscape. Every step of the WGS pipeline, which includes DNA extraction, library preparation, sequencing, bioinformatics analysis, and data storage, is considered with respect to its logistics, necessities, potential pitfalls, and the required quality management. WGS is likely to drive clinical diagnostics and patient care forward, if requirements and challenges of the technique are recognized and met.
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http://dx.doi.org/10.1016/j.semcancer.2021.06.009DOI Listing
June 2021

How artificial intelligence might disrupt diagnostics in hematology in the near future.

Oncogene 2021 Jun 8;40(25):4271-4280. Epub 2021 Jun 8.

MLL Munich Leukemia Laboratory, Munich, Germany.

Artificial intelligence (AI) is about to make itself indispensable in the health care sector. Examples of successful applications or promising approaches range from the application of pattern recognition software to pre-process and analyze digital medical images, to deep learning algorithms for subtype or disease classification, and digital twin technology and in silico clinical trials. Moreover, machine-learning techniques are used to identify patterns and anomalies in electronic health records and to perform ad-hoc evaluations of gathered data from wearable health tracking devices for deep longitudinal phenotyping. In the last years, substantial progress has been made in automated image classification, reaching even superhuman level in some instances. Despite the increasing awareness of the importance of the genetic context, the diagnosis in hematology is still mainly based on the evaluation of the phenotype. Either by the analysis of microscopic images of cells in cytomorphology or by the analysis of cell populations in bidimensional plots obtained by flow cytometry. Here, AI algorithms not only spot details that might escape the human eye, but might also identify entirely new ways of interpreting these images. With the introduction of high-throughput next-generation sequencing in molecular genetics, the amount of available information is increasing exponentially, priming the field for the application of machine learning approaches. The goal of all the approaches is to allow personalized and informed interventions, to enhance treatment success, to improve the timeliness and accuracy of diagnoses, and to minimize technically induced misclassifications. The potential of AI-based applications is virtually endless but where do we stand in hematology and how far can we go?
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http://dx.doi.org/10.1038/s41388-021-01861-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225509PMC
June 2021

Enhancer hijacking drives oncogenic BCL11B expression in lineage ambiguous stem cell leukemia.

Cancer Discov 2021 Jun 8. Epub 2021 Jun 8.

Data Science, Dana-Farber Cancer Institute.

Lineage ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid and stem cell markers driven by aberrant allele-specific deregulation of BCL11B, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose BCL11B to super-enhancers active in hematopoietic progenitors, or focal amplifications that generate a super-enhancer from a non-coding element distal to BCL11B. Chromatin conformation analyses demonstrate long range interactions of rearranged enhancers with the expressed BCL11B allele, and association of BCL11B with activated hematopoietic progenitor cell cis-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic BCL11B expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage ambiguous leukemia.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0145DOI Listing
June 2021

Machine Learning Integrates Genomic Signatures for Subclassification Beyond Primary and Secondary Acute Myeloid Leukemia.

Blood 2021 Jun 1. Epub 2021 Jun 1.

Leukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA, United States.

While genomic alterations drive the pathogenesis of acute myeloid leukemia (AML), traditional classifications are largely based on morphology and prototypic genetic founder lesions define only a small proportion of AML patients. The historical subdivision of primary/de novo AML (pAML) and secondary AML (sAML) has shown to variably correlate with genetic patterns. Perhaps, the combinatorial complexity and heterogeneity of AML genomic architecture have precluded, so far, the genomic-based subclassification to identify distinct molecularly-defined subtypes more reflective of shared pathogenesis. We integrated cytogenetic and gene sequencing data from a multicenter cohort of 6,788 AML patients that were analyzed using standard and machine learning methods to generate a novel AML molecular subclassification with biological correlates corresponding to underlying pathogenesis. Standard supervised analyses resulted in modest cross-validation accuracy when attempting to use molecular patterns to predict traditional pathomorphological AML classifications. We performed unsupervised analysis by applying Bayesian Latent Class method that identified 4 unique genomic clusters of distinct prognoses. Invariant genomic features driving each cluster were extracted and resulted in 97% cross-validation accuracy when used for genomic subclassification. Subclasses of AML defined by molecular signatures overlapped current pathomorphological and clinically-defined AML subtypes. We internally and externally validated our results and share an open-access molecular classification scheme for AML patients. Although the heterogeneity inherent in the genomic changes across nearly 7,000 AML patients is too vast for traditional prediction methods, however, machine learning methods allowed for the definition of novel genomic AML subclasses indicating that traditional pathomorphological definitions may be less reflective of overlapping pathogenesis.
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http://dx.doi.org/10.1182/blood.2020010603DOI Listing
June 2021

Genome-wide DNA methylation analysis pre- and post-lenalidomide treatment in patients with myelodysplastic syndrome with isolated deletion (5q).

Ann Hematol 2021 Jun 27;100(6):1463-1471. Epub 2021 Apr 27.

Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets.
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http://dx.doi.org/10.1007/s00277-021-04492-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116243PMC
June 2021

A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML.

Blood 2021 Jun;137(24):3403-3415

Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.

Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins (FPs) are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of acute myeloid leukemia (AML) driven by the most common AF10 FPs, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a detailed map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent antioncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias.
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http://dx.doi.org/10.1182/blood.2020009023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212510PMC
June 2021

A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.

Blood Cancer Discov 2021 Mar 7;2(2):146-161. Epub 2020 Dec 7.

Department of Translational Hematology and Oncology Research, Taussig Cancer Institute.

is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of and neomorphic mutations, here we report that IDH1/2 mutant-derived 2-hydroxyglutarate is synthetically lethal to TET-dioxygenase deficient cells. In addition, a TET-selective small molecule inhibitor decreased cytosine hydroxymethylation and restricted clonal outgrowth of mutant, but not normal hematopoietic precursor cells and . While TET-inhibitor phenocopied somatic mutations, its pharmacologic effects on normal stem cells were, unlike mutations, reversible. Treatment with TET inhibitor suppressed the clonal evolution of mutant cells in murine models and -mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of targeted agents in mutant neoplasia.
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http://dx.doi.org/10.1158/2643-3230.BCD-20-0173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935131PMC
March 2021

Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond.

Int J Mol Sci 2021 Feb 28;22(5). Epub 2021 Feb 28.

Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria.

Tryptase is a serine protease that is predominantly produced by tissue mast cells (MCs) and stored in secretory granules together with other pre-formed mediators. MC activation, degranulation and mediator release contribute to various immunological processes, but also to several specific diseases, such as IgE-dependent allergies and clonal MC disorders. Biologically active tryptase tetramers primarily derive from the two genes (encoding β-tryptase) and (encoding either α- or β-tryptase). Based on the most common gene copy numbers, three genotypes, 0α:4β, 1α:3β and 2α:2β, were defined as "canonical". About 4-6% of the general population carry germline -α copy number gains (2α:3β, 3α:2β or more α-extra-copies), resulting in elevated basal serum tryptase levels. This condition has recently been termed hereditary alpha tryptasemia (HαT). Although many carriers of HαT appear to be asymptomatic, a number of more or less specific symptoms have been associated with HαT. Recent studies have revealed a significantly higher HαT prevalence in patients with systemic mastocytosis (SM) and an association with concomitant severe Hymenoptera venom-induced anaphylaxis. Moreover, HαT seems to be more common in idiopathic anaphylaxis and MC activation syndromes (MCAS). Therefore, genotyping should be included in the diagnostic algorithm in patients with symptomatic SM, severe anaphylaxis or MCAS.
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http://dx.doi.org/10.3390/ijms22052458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957558PMC
February 2021

The time has come for next-generation sequencing in routine diagnostic workup in hematology

Haematologica 2021 03 1;106(3):659-661. Epub 2021 Mar 1.

MLL Munich Leukemia Laboratory, Munich.

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http://dx.doi.org/10.3324/haematol.2020.270504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927880PMC
March 2021

Precision Medicine in Hematology 2021: Definitions, Tools, Perspectives, and Open Questions.

Hemasphere 2021 Mar 17;5(3):e536. Epub 2021 Feb 17.

Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria.

During the past few years, our understanding of molecular mechanisms and cellular interactions relevant to malignant blood cell disorders has improved substantially. New insights include a detailed knowledge about disease-initiating exogenous factors, endogenous (genetic, somatic, epigenetic) elicitors or facilitators of disease evolution, and drug actions and interactions that underlie efficacy and adverse event profiles in defined cohorts of patients. As a result, precision medicine and personalized medicine are rapidly growing new disciplines that support the clinician in making the correct diagnosis, in predicting outcomes, and in optimally selecting patients for interventional therapies. In addition, precision medicine tools are greatly facilitating the development of new drugs, therapeutic approaches, and new multiparametric prognostic scoring models. However, although the emerging roles of precision medicine and personalized medicine in hematology and oncology are clearly visible, several questions remain. For example, it remains unknown how precision medicine tools can be implemented in healthcare systems and whether all possible approaches are also affordable. In addition, there is a need to define terminologies and to relate these to specific and context-related tools and strategies in basic and applied science. To discuss these issues, a working conference was organized in September 2019. The outcomes of this conference are summarized herein and include a proposal for definitions, terminologies, and applications of precision and personalized medicine concepts and tools in hematologic neoplasms. We also provide proposals aimed at reducing costs, thereby making these applications affordable in daily practice.
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http://dx.doi.org/10.1097/HS9.0000000000000536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892291PMC
March 2021

Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes.

J Clin Oncol 2021 Apr 4;39(11):1223-1233. Epub 2021 Feb 4.

Department of Physics and Astronomy, University of Bologna, Bologna, Italy.

Purpose: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication.

Methods: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed.

Results: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (, , and ) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within - and -related MDS. MDS with complex karyotype and/or gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features.

Conclusion: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.
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http://dx.doi.org/10.1200/JCO.20.01659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078359PMC
April 2021

Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis.

Am J Hum Genet 2021 02 8;108(2):284-294. Epub 2021 Jan 8.

School of Medicine, University of Southampton, Southampton SO17 1BJ, UK.

Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (p = 1.37 × 10, OR = 1.52), rs4662380 (p = 2.11 × 10, OR = 1.46), and rs13077541 (p = 2.10 × 10, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (p = 2.3 × 10), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (p = 2.55 × 10), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (β)-like 1 X-linked receptor 1 (p = 5.70 × 10). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.
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http://dx.doi.org/10.1016/j.ajhg.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895845PMC
February 2021

Malignant Transformation Involving Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia.

Cell Rep Med 2020 Aug 25;1(5):100074. Epub 2020 Aug 25.

Department of Hematology, Erasmus University Medical Center, Rotterdam 3015 CN, the Netherlands.

Severe congenital neutropenia (SCN) patients treated with CSF3/G-CSF to alleviate neutropenia frequently develop acute myeloid leukemia (AML). A common pattern of leukemic transformation involves the appearance of hematopoietic clones with CSF3 receptor () mutations in the neutropenic phase, followed by mutations in before AML becomes overt. To investigate how the combination of CSF3 therapy and and mutations contributes to AML development, we make use of mouse models, SCN-derived induced pluripotent stem cells (iPSCs), and SCN and SCN-AML patient samples. CSF3 provokes a hyper-proliferative state in / mutant hematopoietic progenitors but does not cause overt AML. Intriguingly, an additional acquired driver mutation in causes elevated CXXC4 and reduced TET2 protein levels in murine AML samples. Expression of multiple pro-inflammatory pathways is elevated in mouse AML and human SCN-AML, suggesting that inflammation driven by downregulation of TET2 activity is a critical step in the malignant transformation of SCN.
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http://dx.doi.org/10.1016/j.xcrm.2020.100074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659587PMC
August 2020

Human and artificial intelligence to illuminate MDS.

Blood 2020 11;136(20):2243-2244

MLL Munich Leukemia Laboratory.

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http://dx.doi.org/10.1182/blood.2020008742DOI Listing
November 2020
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