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Article ; Online: The Approach to Thrombosis Prevention across the Spectrum of Philadelphia-Negative Classic Myeloproliferative Neoplasms

Steffen Koschmieder

Hemato, Vol 2, Iss 25, Pp 392-

2021 Volume 402

Abstract: Patients with myeloproliferative neoplasm (MPN) are potentially facing diminished life expectancy and decreased quality of life, due to thromboembolic and hemorrhagic complications, progression to myelofibrosis or acute leukemia with ensuing signs of ... ...

Abstract	Patients with myeloproliferative neoplasm (MPN) are potentially facing diminished life expectancy and decreased quality of life, due to thromboembolic and hemorrhagic complications, progression to myelofibrosis or acute leukemia with ensuing signs of hematopoietic insufficiency, and disturbing symptoms such as pruritus, night sweats, and bone pain. In patients with essential thrombocythemia (ET) or polycythemia vera (PV), current guidelines recommend both primary and secondary measures to prevent thrombosis. These include acetylsalicylic acid (ASA) for patients with intermediate- or high-risk ET and all patients with PV, unless they have contraindications for ASA use, and phlebotomy for all PV patients. A target hematocrit level below 45% is demonstrated to be associated with decreased cardiovascular events in PV. In addition, cytoreductive therapy is shown to reduce the rate of thrombotic complications in high-risk ET and high-risk PV patients. In patients with prefibrotic primary myelofibrosis (pre-PMF), similar measures are recommended as in those with ET. Patients with overt PMF may be at increased risk of bleeding and thus require a more individualized approach to thrombosis prevention. This review summarizes the thrombotic risk factors and primary and secondary preventive measures against thrombosis in MPN.
Keywords	myeloproliferative neoplasms (MPN) ; polycythemia vera (PV) ; essential thrombocythemia (ET) ; primary myelofibrosis (PMF) ; thrombosis ; prevention ; Medicine ; R
Subject code	610
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Quantification of hematopoietic stem and progenitor cells by targeted DNA methylation analysis

Ledio Bocova / Wouter Hubens / Cordula Engel / Steffen Koschmieder / Edgar Jost / Wolfgang Wagner

Clinical Epigenetics, Vol 15, Iss 1, Pp 1-

2023 Volume 6

Abstract: Abstract Hematopoietic stem and progenitor cells (HSPCs) are quantified in daily clinical practice by flow cytometry. In this study, we provide proof of concept that HSPCs can also be estimated by targeted DNA methylation (DNAm) analysis. The DNAm levels ...

Abstract	Abstract Hematopoietic stem and progenitor cells (HSPCs) are quantified in daily clinical practice by flow cytometry. In this study, we provide proof of concept that HSPCs can also be estimated by targeted DNA methylation (DNAm) analysis. The DNAm levels at three individual CG dinucleotides (CpG sites) in the genes MYO1D, STK17A, and SP140 correlated with CD34+ cell numbers in mobilized peripheral blood and with blast counts in leukemia. In the future, such epigenetic biomarkers can support the evaluation of stem cell mobilization, HSPC harvesting, or blast count in leukemia.
Keywords	DNA methylation ; Biomarker ; Epigenetic ; Hematopoietic stem cells ; HSC ; CD34 ; Medicine ; R ; Genetics ; QH426-470
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Progression of Myeloproliferative Neoplasms (MPN)

Julian Baumeister / Nicolas Chatain / Alexandros Marios Sofias / Twan Lammers / Steffen Koschmieder

Cells, Vol 10, Iss 3551, p

Diagnostic and Therapeutic Perspectives

2021 Volume 3551

Abstract: Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. ... ...

Abstract	Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one of the major causes of morbidity and mortality. There are clinically evident but also subclinical types of MPN progression. Clinically evident progression includes evolution from ET to PV, ET to post-ET-MF, PV to post-PV-MF, or pre-PMF to overt PMF, and transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia. Thrombosis, major hemorrhage, severe infections, or increasing symptom burden (e.g., pruritus, night sweats) may herald progression. Subclinical types of progression may include increases in the extent of bone marrow fibrosis, increases of driver gene mutational allele burden, and clonal evolution. The underlying causes of MPN progression are diverse and can be attributed to genetic alterations and chronic inflammation. Particularly, bystander mutations in genes encoding epigenetic regulators or splicing factors were associated with progression. Finally, comorbidities such as systemic inflammation, cardiovascular diseases, and organ fibrosis may augment the risk of progression. The aim of this review was to discuss types and mechanisms of MPN progression and how their knowledge might improve risk stratification and therapeutic intervention. In view of these aspects, we discuss the potential benefits of early diagnosis using molecular and functional imaging and exploitable therapeutic strategies that may prevent progression, but also highlight current challenges and methodological pitfalls.
Keywords	MPN ; progression ; diagnosis ; therapy ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Exploiting Synthetic Lethality between Germline BRCA1 Haploinsufficiency and PARP Inhibition in JAK2V617F-Positive Myeloproliferative Neoplasms

Max Bermes / Maria Jimena Rodriguez / Marcelo Augusto Szymanski de Toledo / Sabrina Ernst / Gerhard Müller-Newen / Tim Henrik Brümmendorf / Nicolas Chatain / Steffen Koschmieder / Julian Baumeister

International Journal of Molecular Sciences, Vol 24, Iss 24, p

2023 Volume 17560

Abstract: Myeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break ...

Abstract	Myeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break repair genes (e.g., BRCA1 ). We investigated the therapeutic potential of targeting BRCA1 haploinsufficiency alongside the JAK2 V617F driver mutation. We assessed the efficacy of combining the PARP inhibitor olaparib with interferon-alpha (IFNα) in CRISPR/Cas9-engineered Brca1 +/− Jak2 V617F-positive 32D cells. Olaparib treatment induced a higher number of DNA double-strand breaks, as demonstrated by γH2AX analysis through Western blot ( p = 0.024), flow cytometry ( p = 0.013), and confocal microscopy ( p = 0.071). RAD51 foci formation was impaired in Brca1 +/− cells compared to Brca1 +/+ cells, indicating impaired homologous recombination repair due to Brca1 haploinsufficiency. Importantly, olaparib enhanced apoptosis while diminishing cell proliferation and viability in Brca1 +/− cells compared to Brca1 +/+ cells. These effects were further potentiated by IFNα. Olaparib induced interferon-stimulated genes and increased endogenous production of IFNα in Brca1 +/− cells. These responses were abrogated by STING inhibition. In conclusion, our findings suggest that the combination of olaparib and IFNα presents a promising therapeutic strategy for MPN patients by exploiting the synthetic lethality between germline BRCA1 mutations and the JAK2 V617F MPN driver mutation.
Keywords	myeloproliferative neoplasms ; MPN ; BRCA1 ; haploinsufficiency ; olaparib ; interferon-alpha ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: KIT D816V Mast Cells Derived from Induced Pluripotent Stem Cells Recapitulate Systemic Mastocytosis Transcriptional Profile

Marcelo A. S. de Toledo / Xuhuang Fu / Tiago Maié / Eva M. Buhl / Katrin Götz / Susanne Schmitz / Anne Kaiser / Peter Boor / Till Braunschweig / Nicolas Chatain / Ivan G. Costa / Tim H. Brümmendorf / Steffen Koschmieder / Martin Zenke

International Journal of Molecular Sciences, Vol 24, Iss 5275, p

2023 Volume 5275

Abstract: Mast cells (MCs) represent a population of hematopoietic cells with a key role in innate and adaptive immunity and are well known for their detrimental role in allergic responses. Yet, MCs occur in low abundance, which hampers their detailed molecular ... ...

Abstract	Mast cells (MCs) represent a population of hematopoietic cells with a key role in innate and adaptive immunity and are well known for their detrimental role in allergic responses. Yet, MCs occur in low abundance, which hampers their detailed molecular analysis. Here, we capitalized on the potential of induced pluripotent stem (iPS) cells to give rise to all cells in the body and established a novel and robust protocol for human iPS cell differentiation toward MCs. Relying on a panel of systemic mastocytosis (SM) patient-specific iPS cell lines carrying the KIT D816V mutation, we generated functional MCs that recapitulate SM disease features: increased number of MCs, abnormal maturation kinetics and activated phenotype, CD25 and CD30 surface expression and a transcriptional signature characterized by upregulated expression of innate and inflammatory response genes. Therefore, human iPS cell-derived MCs are a reliable, inexhaustible, and close-to-human tool for disease modeling and pharmacological screening to explore novel MC therapeutics.
Keywords	mast cell ; systemic mastocytosis ; KIT D816V ; induced pluripotent stem cell ; disease modeling ; RNA-seq ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CRISPR/Cas9-engineered human ES cells harboring heterozygous and homozygous c-KIT knockout

Marcelo A.S. de Toledo / Xuhuang Fu / Frederick Kluge / Katrin Götz / Susanne Schmitz / Paul Wanek / Herdit M. Schüler / Kristina Pannen / Nicolas Chatain / Steffen Koschmieder / Tim H. Brümmendorf / Martin Zenke

Stem Cell Research, Vol 60, Iss , Pp 102732- (2022)

2022

Abstract: The receptor tyrosine kinase c-KIT (CD117) has a key role in hematopoiesis and is a marker for endothelial and cardiac progenitor cells. In vivo, deficiency of c-KIT is lethal and therefore using CRISPR/Cas9 editing we generated heterozygous and ... ...

Abstract	The receptor tyrosine kinase c-KIT (CD117) has a key role in hematopoiesis and is a marker for endothelial and cardiac progenitor cells. In vivo, deficiency of c-KIT is lethal and therefore using CRISPR/Cas9 editing we generated heterozygous and homozygous c-KIT knockout human embryonic stem cell (ES cell) lines. The c-KIT knockout left ES cell pluripotency unaffected as shown by immunofluorescence and trilineage differentiation potential. Heterozygous and homozygous c-KIT knockouts showed complete loss of exon 17, resulting in ablation of c-KIT protein from the cell surface. c-KIT knockout ES cells provide a valuable tool for further investigating c-KIT biology.
Keywords	Embryonic stem cells ; ES cells ; c-KIT ; CD117 ; Stem cell factor receptor ; CRISPR ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Novel homozygous nonsense mutation in the P5′N‐1 coding gene as an alternative cause for hereditary anemia with basophilic stippling

Martin Kirschner / Inga Rebecca Heinen / Steffen Koschmieder / Licinio Manco / Celeste Bento / Thomas Eggermann / Ingo Kurth / Edgar Jost / Tim H. Brümmendorf / Roland Fuchs

Clinical Case Reports, Vol 10, Iss 3, Pp n/a-n/a (2022)

2022

Abstract: Abstract Hereditary pyrimidine 5‐nucleotidase (P5′N‐1) deficiency is a very rare disorder. Here, we describe a new mutation in a Turkish family. Although functional tests have not been performed, our findings confirm that the homozygous mutational state ... ...

Abstract	Abstract Hereditary pyrimidine 5‐nucleotidase (P5′N‐1) deficiency is a very rare disorder. Here, we describe a new mutation in a Turkish family. Although functional tests have not been performed, our findings confirm that the homozygous mutational state leads to clinical manifest P5′N‐1 deficiency, while heterozygosity does not lead to hemolysis or anemia.
Keywords	basophilic stippling ; hemolysis ; hereditary anemia ; pyrimidine 5‐nucleotidase (P5′N‐1) deficiency ; Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CRISPR/Cas9 mediated CXCL4 knockout in human iPS cells of polycythemia vera patient with JAK2 V617F mutation

Janik Boehnke / Salim Atakhanov / Marcelo A.S. Toledo / Herdit M. Schüler / Stephanie Sontag / Nicolas Chatain / Steffen Koschmieder / Tim H. Brümmendorf / Rafael Kramann / Martin Zenke

Stem Cell Research, Vol 55, Iss , Pp 102490- (2021)

2021

Abstract: The chemokine CXCL4/platelet factor 4 (PF4) gene, a key player in myelofibrosis, was knocked out by CRISPR/Cas9 in induced pluripotent stem cells (iPS cells) of a polycythemia vera (PV) patient with JAK2 V617F mutation. Two CXCL4KO iPS cell lines with ... ...

Abstract	The chemokine CXCL4/platelet factor 4 (PF4) gene, a key player in myelofibrosis, was knocked out by CRISPR/Cas9 in induced pluripotent stem cells (iPS cells) of a polycythemia vera (PV) patient with JAK2 V617F mutation. Two CXCL4KO iPS cell lines with and without JAK2 V617F mutation (UKAi002-B-1 and UKAi002-A-1, respectively) were generated. CXCL4KO iPS cells showed deletion of exon 1 and complete loss of CXCL4 protein. Pluripotency of iPS cells was confirmed by expression of pluripotency markers and trilineage differentiation. CXCL4KO iPS cells are expected to provide a valuable tool for investigating the role of CXCL4 in human diseases.
Keywords	Induced pluripotent stem cell ; iPS cells ; Hematopoiesis ; CXCL4 ; PF4 ; JAK2 V617F ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms

Jessica E. Pritchard / Juliette E. Pearce / Inge A.M. Snoeren / Stijn N.R. Fuchs / Katrin Götz / Fabian Peisker / Silke Wagner / Adam Benabid / Niklas Lutterbach / Vanessa Klöker / James S. Nagai / Monica T. Hannani / Anna K. Galyga / Ellen Sistemich / Bella Banjanin / Niclas Flosdorf / Eric Bindels / Kathrin Olschok / Katharina Biaesch /

Nicolas Chatain / Neha Bhagwat / Andrew Dunbar / Rita Sarkis / Olaia Naveiras / Marie-Luise Berres / Steffen Koschmieder / Ross L. Levine / Ivan G. Costa / Hélène F.E. Gleitz / Rafael Kramann / Rebekka K. Schneider

Cell Reports, Vol 43, Iss 1, Pp 113608- (2024)

1481

Abstract: Summary: The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically ... ...

Abstract	Summary: The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.
Keywords	CP: Stem cell research ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Serum of myeloproliferative neoplasms stimulates hematopoietic stem and progenitor cells.

Richard K Lubberich / Thomas Walenda / Tamme W Goecke / Klaus Strathmann / Susanne Isfort / Tim H Brümmendorf / Steffen Koschmieder / Wolfgang Wagner

PLoS ONE, Vol 13, Iss 5, p e

2018 Volume 0197233

Abstract: Myeloproliferative neoplasms (MPN)-such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF)-are typically diseases of the elderly caused by acquired somatic mutations. However, it is largely unknown how the malignant clone ... ...

Abstract	Myeloproliferative neoplasms (MPN)-such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF)-are typically diseases of the elderly caused by acquired somatic mutations. However, it is largely unknown how the malignant clone interferes with normal hematopoiesis. In this study, we analyzed if serum of MPN patients comprises soluble factors that impact on hematopoietic stem and progenitor cells (HPCs).CD34+ HPCs were cultured in medium supplemented with serum samples of PV, ET, or MF patients, or healthy controls. The impact on proliferation, maintenance of immature hematopoietic surface markers, and colony forming unit (CFU) potential was systematically analyzed. In addition, we compared serum of healthy young (<25 years) and elderly donors (>50 years) to determine how normal aging impacts on the hematopoiesis-supportive function of serum.Serum from MF, PV and ET patients significantly increased proliferation as compared to controls. In addition, serum from MF and ET patients attenuated the loss of a primitive immunophenotype during in vitro culture. The CFU counts were significantly higher if HPCs were cultured with serum of MPN patients as compared to controls. Furthermore, serum of healthy young versus old donors did not evoke significant differences in proliferation or immunophenotype of HPCs, whereas the CFU frequency was significantly increased by serum from elderly patients.Our results indicate that serum derived from patients with MPN comprises activating feedback signals that stimulate the HPCs-and this stimulatory signal may result in a viscous circle that further accelerates development of the disease.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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