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  1. Article: Characterization of engraftment dynamics in myelofibrosis after allogeneic hematopoietic cell transplantation including novel conditioning schemes.

    Jungius, Sarah / Adam, Franziska C / Grosheintz, Kerstin / Medinger, Michael / Buser, Andreas / Passweg, Jakob R / Halter, Jörg P / Meyer, Sara C

    Frontiers in oncology

    2023  Volume 13, Page(s) 1205387

    Abstract: Introduction: Myelofibrosis (MF) is a rare hematopoietic stem cell disorder progressing to bone marrow (BM) failure or blast phase. Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative therapy for a limited subset of ... ...

    Abstract Introduction: Myelofibrosis (MF) is a rare hematopoietic stem cell disorder progressing to bone marrow (BM) failure or blast phase. Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative therapy for a limited subset of patients with advanced MF, who are eligible, but engraftment in MF vs. AML is delayed which promotes complications. As determinants of engraftment in MF are incompletely characterized, we studied engraftment dynamics at our center.
    Methods: A longitudinal cohort of 71 allogeneic HCT performed 2000-2019 with >50% after 2015 was evaluated.
    Results: Median time to neutrophil engraftment ≥0.5x109/l was +20 days post-transplant and associated with BM fibrosis, splenomegaly and infused CD34+ cell number. Engraftment dynamics were similar in primary vs. secondary MF and were independent of MF driver mutations in JAK2, CALR and MPL. Neutrophil engraftment occurred later upon haploidentical HCT with thiotepa-busulfan-fludarabine conditioning, post-transplant cyclophosphamide and G-CSF (TBF-PTCy/G-CSF) administered to 9.9% and 15.6% of patients in 2000-2019 and after 2015, respectively. Engraftment of platelets was similarly delayed, while reconstitution of reticulocytes was not affected.
    Conclusions: Since MF is a rare hematologic malignancy, this data from a large number of HCT for MF is essential to substantiate that later neutrophil and platelet engraftment in MF relates both to host and treatment-related factors. Observations from this longitudinal cohort support that novel conditioning schemes administered also to rare entities such as MF, require detailed evaluation in larger, multi-center cohorts to assess also indicators of long-term graft function and overall outcome in patients with this infrequent hematopoietic neoplasm undergoing allogeneic transplantation.
    Language English
    Publishing date 2023-08-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2023.1205387
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Development of Resistance to Type II JAK2 Inhibitors in MPN Depends on AXL Kinase and Is Targetable.

    Codilupi, Tamara / Szybinski, Jakub / Arunasalam, Stefanie / Jungius, Sarah / Dunbar, Andrew C / Stivala, Simona / Brkic, Sime / Albrecht, Camille / Vokalova, Lenka / Yang, Julie L / Buczak, Katarzyna / Ghosh, Nilabh / Passweg, Jakob R / Rovo, Alicia / Angelillo-Scherrer, Anne / Pankov, Dmitry / Dirnhofer, Stefan / Levine, Ross L / Koche, Richard /
    Meyer, Sara C

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2023  Volume 30, Issue 3, Page(s) 586–599

    Abstract: Purpose: Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Because clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We ... ...

    Abstract Purpose: Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Because clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition.
    Experimental design: MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC/RNA sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice.
    Results: MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2,500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NOD/SCID gamma mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Because inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL/MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line-derived mouse model, marrow infiltration was decreased supporting dependency on AXL/MAPK.
    Conclusions: We report on a novel mechanism of AXL/MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN.
    MeSH term(s) Animals ; Mice ; Cell Line, Tumor ; Protein Kinase Inhibitors/pharmacology ; Mice, Inbred NOD ; Mice, SCID ; Janus Kinase Inhibitors ; Janus Kinase 2/metabolism ; Myeloproliferative Disorders/drug therapy ; Myeloproliferative Disorders/genetics ; Myeloproliferative Disorders/metabolism ; Aminopyridines ; Benzimidazoles
    Chemical Substances CHZ868 ; Protein Kinase Inhibitors ; Janus Kinase Inhibitors ; Janus Kinase 2 (EC 2.7.10.2) ; Aminopyridines ; Benzimidazoles
    Language English
    Publishing date 2023-11-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-23-0163
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Dual targeting of JAK2 and ERK interferes with the myeloproliferative neoplasm clone and enhances therapeutic efficacy.

    Brkic, Sime / Stivala, Simona / Santopolo, Alice / Szybinski, Jakub / Jungius, Sarah / Passweg, Jakob R / Tsakiris, Dimitrios / Dirnhofer, Stefan / Hutter, Gregor / Leonards, Katharina / Lischer, Heidi E L / Dettmer, Matthias S / Neel, Benjamin G / Levine, Ross L / Meyer, Sara C

    Leukemia

    2021  Volume 35, Issue 10, Page(s) 2875–2884

    Abstract: Myeloproliferative neoplasms (MPN) show dysregulated JAK2 signaling. JAK2 inhibitors provide clinical benefits, but compensatory activation of MAPK pathway signaling impedes efficacy. We hypothesized that dual targeting of JAK2 and ERK1/2 could enhance ... ...

    Abstract Myeloproliferative neoplasms (MPN) show dysregulated JAK2 signaling. JAK2 inhibitors provide clinical benefits, but compensatory activation of MAPK pathway signaling impedes efficacy. We hypothesized that dual targeting of JAK2 and ERK1/2 could enhance clone control and therapeutic efficacy. We employed genetic and pharmacologic targeting of ERK1/2 in Jak2V617F MPN mice, cells and patient clinical isolates. Competitive transplantations of Jak2V617F vs. wild-type bone marrow (BM) showed that ERK1/2 deficiency in hematopoiesis mitigated MPN features and reduced the Jak2V617F clone in blood and hematopoietic progenitor compartments. ERK1/2 ablation combined with JAK2 inhibition suppressed MAPK transcriptional programs, normalized cytoses and promoted clone control suggesting dual JAK2/ERK1/2 targeting as enhanced corrective approach. Combined pharmacologic JAK2/ERK1/2 inhibition with ruxolitinib and ERK inhibitors reduced proliferation of Jak2V617F cells and corrected erythrocytosis and splenomegaly of Jak2V617F MPN mice. Longer-term treatment was able to induce clone reductions. BM fibrosis was significantly decreased in MPLW515L-driven MPN to an extent not seen with JAK2 inhibitor monotherapy. Colony formation from JAK2V617F patients' CD34
    MeSH term(s) Animals ; Cell Proliferation ; Female ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Janus Kinase 2/antagonists & inhibitors ; Janus Kinase 2/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitogen-Activated Protein Kinase 1/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 1/physiology ; Mitogen-Activated Protein Kinase 3/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 3/physiology ; Myeloproliferative Disorders/drug therapy ; Myeloproliferative Disorders/metabolism ; Myeloproliferative Disorders/pathology ; Nitriles/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology
    Chemical Substances Nitriles ; Protein Kinase Inhibitors ; Pyrazoles ; Pyrimidines ; ruxolitinib (82S8X8XX8H) ; Jak2 protein, mouse (EC 2.7.10.2) ; Janus Kinase 2 (EC 2.7.10.2) ; Mapk1 protein, mouse (EC 2.7.11.24) ; Mapk3 protein, mouse (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
    Language English
    Publishing date 2021-09-03
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 807030-1
    ISSN 1476-5551 ; 0887-6924
    ISSN (online) 1476-5551
    ISSN 0887-6924
    DOI 10.1038/s41375-021-01391-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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