Biological drivers of clinical phenotype in myelofibrosis

Mascarenhas, John; Gleitz, Hélène; Chifotides, Helen T.; Harrison, Claire; Verstovšek, Srđan; Vannucchi, Alessandro M.; Rampal, Raajit K.; Kiladjian, Jean‐Jacques; Vainchenker, William; Hoffman, Ronald; Schneider, Rebekka K.; List, Alan F.

doi:10.1038/s41375-022-01767-y

Cited by 30 publications

(36 citation statements)

References 127 publications

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“…While JAK inhibitors (JAKi), such as Ruxolitinib, have shown significant improvements, their efficacy is limited on reducing malignant clonal burden and MF progression [3]. Despite the homogenous mutational landscape of MPNs, the underlying pathobiological mechanisms of MF are not fully understood [4,5]. It has long been hypothesized that mutated clonal cells, including hematopoietic stem cells (HSCs), megakaryocytes (Mks) and monocytes, contribute to the aberrant cytokine storm responsible for immune reactions and activation of fibrosis-promoting cellular drivers [6,7].…”

Section: Introductionmentioning

confidence: 99%

Inflammation and bone marrow fibrosis: novel immunotherapeutic targets

Calledda,

Malara,

Balduini

2023

Current Opinion in Hematology

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Purpose of review Myelofibrosis (MF) is primarily driven by constitutive activation of the Janus kinase/signal transducer of activators of transcription (JAK/STAT) pathway. While JAK inhibitors have shown to alleviate disease symptoms, their disease-modifying effects in MF are limited. The only curative treatment remains allogeneic stem cell transplantation, which can be applied to a minority of patients. As a result, there is a need to explore novel targets in MF to facilitate appropriate drug development and therapeutic pathways. Recent findings Recent research has focused on identifying novel signals that contribute to the abnormal cross-talk between hematopoietic and stromal cells, which promotes MF and disease progression. Inflammation and immune dysregulation have emerged as key drivers of both the initiation and progression of MF. A growing number of actionable targets has been identified, including cytokines, transcription factors, signalling networks and cell surface-associated molecules. These targets exhibit dysfunctions in malignant and nonmalignant hematopoietic cells, but also in nonhematopoietic cells of the bone marrow. The study of these inflammation-related molecules, in preclinical models and MF patient's samples, is providing novel therapeutic targets. Summary The identification of immunotherapeutic targets is expanding the therapeutic landscape of MF. This review provides a summary of the most recent advancements in the study of immunotherapeutic targets in MF.

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Section: Introductionmentioning

confidence: 99%

Inflammation and bone marrow fibrosis: novel immunotherapeutic targets

Calledda,

Malara,

Balduini

2023

Current Opinion in Hematology

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“…2019; Fisher et al . 2021; Mascarenhas et al, 2022), leading to the hypothesis that unregulated TLR, and/or TPO signalling could be responsible for triggering chronic inflammation. This would then perturb the BM microenvironment and disrupt the crosstalk between HSCs and MSCs and lead to HSC migration and disease development.…”

Section: Introductionmentioning

confidence: 99%

“…Chronic inflammation is believed to result in a break in any of these communication pathways which leads to HSC migration (Caocci et al 2017). ligand-activated stimulation of Toll-Like Receptors (TLRs) are well documented to induce chronic inflammation (Desterke et al 2015;Fisher et al 2017;Fisher et al 2019;Fisher et al 2021;Mascarenhas et al, 2022), leading to the hypothesis that unregulated TLR, and/or TPO signalling could be responsible for triggering chronic inflammation. This would then perturb the BM microenvironment and disrupt the crosstalk between HSCs and MSCs and lead to HSC migration and disease development.…”

Section: Introductionmentioning

confidence: 99%

Logical modelling of myelofibrotic microenvironment predicts dysregulated progenitor stem cell crosstalk

Chapman

Duprez

Rémy

2022

Preprint

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Primary myelofibrosis is an untreatable age-related disorder of haematopoiesis in which a break in the crosstalk between progenitor Haematopoietic Stem Cells (HSCs) and neighbouring mesenchymal stem cells causes HSCs to rapidly proliferate and migrate out of the bone marrow. 90% of patients harbour mutations in driver genes that all converge to overactivate hematopoietic JAK-STAT signalling, which is thought to be critical for disease progression, as well as microenvironment modification induced by chronic inflammation. The trigger to the initial event is unknown but dysregulated thrombopoietin (TPO) and Toll-Like Receptor (TLR) signalling are hypothesised to initiate chronic inflammation which then disrupts stem cell crosstalk. Using a systems biology approach, we have constructed an inter and intracellular logical model that captures JAK-STAT signalling and key crosstalk channels between haematopoietic and mesenchymal stem cells. The aim of the model is to decipher how TPO and TLR stimulation can perturb the bone marrow microenvironment and dysregulate stem cell crosstalk. The model predicted conditions in which the disease was averted and established for both wildtype and ectopically JAK mutated simulations. The presence of TPO and TLR are both required to disturb stem cell crosstalk and result in the disease for wildtype. TLR signalling alone was sufficient to perturb the crosstalk and drive disease progression for JAK mutated simulations. Furthermore, the model predicts the probability of disease onset for wildtype simulations that matches clinical data. These predictions might explain why patients who test negative for the JAK mutation can still be diagnosed with PMF, in which continual exposure to TPO and TLR receptor activation may trigger the initial inflammatory event that perturbs the bone marrow microenvironment and induce disease onset.

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“…The myelodepletive-cytopenic phenotype of MF is characterized by a low JAK2V617F VAF frequency or a wild-type JAK2 and somatic mutations involving the spliceosome, epigenetic, and apoptosis pathways. 39 Myeloid mutations including HMR and U2AF1 mutations are enriched in cytopenic MF patients, suggesting that this phenotype is caused less by JAK/STAT activating mutations and more by the evolution of an aggressive subclone with several clonal driver mutations. 39,40 The myelodepletive phenotype is more frequently observed in PMF patients and is associated with a shortened survival.…”

mentioning

confidence: 99%

“…39 Myeloid mutations including HMR and U2AF1 mutations are enriched in cytopenic MF patients, suggesting that this phenotype is caused less by JAK/STAT activating mutations and more by the evolution of an aggressive subclone with several clonal driver mutations. 39,40 The myelodepletive phenotype is more frequently observed in PMF patients and is associated with a shortened survival.…”

mentioning

confidence: 99%