Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice

Leiva, Orly; Ng, Seng Kah; Matsuura, Shinobu; Chitalia, Vipul C.; Lucero, Héctor A.; Findlay, Alison D.; Turner, Catherine; Jarolimek, Wolfgang; Ravid, Katya

doi:10.1007/s12185-019-02751-6

Cited by 31 publications

(36 citation statements)

References 32 publications

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“…As described above, LOXs play a key role in this process by cross-linking collagens and elastins through the deamination of lysins and hydroxylysins [ 98 ]. However, simtuzumab, a humanized monoclonal antibody targeting lysyl oxidase-like 2 (LOXL2), failed to meet expectations from in vitro studies [ 172 , 173 ], when tested in a phase II clinical trial of MF patients [ 174 ].…”

Section: Looking For the Achilles’ Heel In Mpns: Innovative Targetmentioning

confidence: 99%

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

Nasillo

Riva

Paolini

et al. 2021

IJMS

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The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.

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Section: Looking For the Achilles’ Heel In Mpns: Innovative Targetmentioning

confidence: 99%

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

Nasillo

Riva

Paolini

et al. 2021

IJMS

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“…Lysyl oxidases are expressed in immature megakaryocytes and downregulated in mature megakaryocytes but upregulated in MF patient megakaryocytes and in murine models of MF ( 38 , 92 , 93 ). Lysyl oxidase inhibition has shown efficacy in Gata1 low ( 38 ) and JAK2 V617F mouse models of MF ( 94 – 96 ). However a recent phase 2 study of simtuzumab, a monoclonal inhibitor of LOX2 did not reduce bone fibrosis in patients with MF ( 97 ).…”

Section: Therapeutic Targeting Of Soluble Mediators the Malignant Bomentioning

confidence: 99%

Remodeling the Bone Marrow Microenvironment – A Proposal for Targeting Pro-inflammatory Contributors in MPN

Jutzi

Mullally

2020

Front. Immunol.

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Philadelphia-negative myeloproliferative neoplasms (MPN) are malignant bone marrow (BM) disorders, typically arising from a single somatically mutated hematopoietic stem cell. The most commonly mutated genes, JAK2 , CALR , and MPL lead to constitutively active JAK-STAT signaling. Common clinical features include myeloproliferation, splenomegaly and constitutional symptoms. This review covers the contributions of cellular components of MPN pathology (e.g., monocytes, megakaryocytes, and mesenchymal stromal cells) as well as cytokines and soluble mediators to the development of myelofibrosis (MF) and highlights recent therapeutic advances. These findings outline the importance of malignant and non-malignant BM constituents to the pathogenesis and treatment of MF.

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“…The mechanisms behind increased thrombotic risk in MPNs may also be related to increased JAK-STAT signaling and inflammation [ 60 ]. Other potential mechanisms for thrombosis include the upregulation of lysyl oxidase (LOX), an enzyme more commonly known to be involved in collagen cross-linking but may also increase platelet reactivity and thrombosis risk [ 79 , 80 , 81 ]. Nasser and colleagues provide a comprehensive review of the mechanisms behind hypercoagulability in cancer patients that is beyond the scope of this review [ 82 ].…”

Section: Potential Mechanisms Of Increased Thrombotic Riskmentioning

confidence: 99%

Impact of Tumor Genomic Mutations on Thrombotic Risk in Cancer Patients

Leiva

Connors

Al‐Samkari

2020

Cancers

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Venous thromboembolism (VTE) is common in patients with cancer and is an important contributor to morbidity and mortality in these patients. Early thromboprophylaxis initiated only in those cancer patients at highest risk for VTE would be optimal. Risk stratification scores incorporating tumor location, laboratory values and patient characteristics have attempted to identify those patients most likely to benefit from thromboprophylaxis but even well-validated scores are not able to reliably distinguish the highest-risk patients. Recognizing that tumor genetics affect the biology and behavior of malignancies, recent studies have explored the impact of specific molecular aberrations on the rate of VTE in cancer patients. The presence of certain molecular aberrations in a variety of different cancers, including lung, colon, brain and hematologic tumors, have been associated with an increased risk of VTE and arterial thrombotic events. This review examines the findings of these studies and discusses the implications of these findings on decisions relating to thromboprophylaxis use in the clinical setting. Ultimately, the integration of tumor molecular genomic information into clinical VTE risk stratification scores in cancer patients may prove to be a major advancement in the prevention of cancer-associated thrombosis.

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Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice

Cited by 31 publications

References 32 publications

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

Remodeling the Bone Marrow Microenvironment – A Proposal for Targeting Pro-inflammatory Contributors in MPN

Impact of Tumor Genomic Mutations on Thrombotic Risk in Cancer Patients

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