Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies

Zahr, Abdallah Abou; Salama, Mohamed E.; Carreau, Nicole; Tremblay, Douglas; Verstovšek, Srđan; Mesa, Ruben A.; Hoffman, Ronald; Mascarenhas, John

doi:10.3324/haematol.2015.141283

Cited by 125 publications

(109 citation statements)

References 90 publications

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“…120 Simtuzumab, a humanized antibody against LOXL2, was used in 54 patients with MF; treatment was well tolerated, but no clear signal of response was observed. 121 Other emerging therapies: CRISPR and immunotherapy CRISPR/Cas9 is a novel genome editing technology that allows for targeting and modifying specific sites in the genome and that is becoming a major avenue for gene therapy. 122,123 Using induced pluripotent stem cells as a model, specific target of the JAK2V617F mutated allele over the wild-type was demonstrated, 124 speaking in support of its potential for treating these diseases.…”

Section: Antifibrotic Agentsmentioning

confidence: 99%

Emerging treatments for classical myeloproliferative neoplasms

Vannucchi

Harrison

2017

Blood

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There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients’ major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.

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Section: Antifibrotic Agentsmentioning

confidence: 99%

Emerging treatments for classical myeloproliferative neoplasms

Vannucchi

Harrison

2017

Blood

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“…We could speculate that elevated endoplasmic reticulum stress induces the release of damage-associated molecular patterns to the tumor microenvironment, which activates IFN-gamma signaling in PMF cells. The elevated IFN-gamma signaling induces higher activity in the IPs, which might improve antigen presentation and result in the recruitment of TILs to the bone marrow, the release of pro-inflammatory cytokine and as a consequence, the increase of fibrosis [67]. In this regard, the activation of IPs determines the ability of the PMF cells to be potentially recognized by cytotoxic CD8 + cells (Figure 8).…”

Section: Discussionmentioning

confidence: 99%

Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients

Rosa

Giallongo

Romano

et al. 2020

IJMS

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Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by stem-cell-derived clonal over-proliferation of mature myeloid lineages, bone marrow fibrosis, osteosclerosis, defective erythropoiesis, and pro-inflammatory cytokine over-expression. The aim of the present study was to highlight possible differences in the transcriptome among CD34+ cells from peripheral blood (PB) of PMF patients. Therefore, we merged two microarray datasets of healthy control subjects and PMF (34 JAK2V617F MUTATED and 28 JAK2 wild-type). The GO analysis of upregulated genes revealed enrichment for JAK2/STAT1 pathway gene set in PB CD34+ cells of PMF patients with and without the JAK2V617F mutation comparing to the healthy control subjects, and in particular a significant upregulation of immunoproteasome (IP)-belonging genes as PSMB8, PSMB9, and PSMB10. A more detailed investigation of the IFN-gamma (IFNG) pathway also revealed that IFNG, IRF1, and IFNGR2 were significantly upregulated in PB CD34+ cells of PMF patients carrying the mutation for JAK2V617F compared to JAK2 wild-type PMF patients. Finally, we showed an upregulation of HLA-class I genes in PB CD34+ cells from PMF JAK2V617F mutated patients compared to JAK2 wild-type and healthy controls. In conclusion, our results demonstrate that IPs and IFNG pathways could be involved in PMF disease and in particular in patients carrying the JAK2V617F mutation.

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“…To delineate the candidate pathways that might be involved in the transformation, we employed GSEA and identified a subset of miR-21-targeted genes that were down-regulated in this sample ( Fig 3C). With transforming growth factor beta (TGF-b, also termed TGFB1) being a known regulator of miR-21 (Bhagat et al, 2013) and a central player in the pathogenesis of MF, (Zahr et al, 2016) we checked and found an inverse correlation in the activity of TGF-b signalling between them ( Fig 3D). We speculated that dysregulated interacting miR-21/TGF-b pathway might participate in secondary MF transformation ( Fig 3E).…”

Section: Heterogeneity Similarly Exists In Patients With Identical Drmentioning

confidence: 99%

Molecular heterogeneity unravelled by single‐cell transcriptomics in patients with essential thrombocythaemia

et al. 2019

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Summary Significant phenotypic heterogeneity exists in patients with all subtypes of myeloproliferative neoplasms (MPN), including essential thrombocythaemia (ET). Single‐cell RNA sequencing (scRNA‐Seq) holds the promise of unravelling the biology of MPN at an unprecedented level of resolution. Herein we employed this approach to dissect the transcriptomes in the CD34+ cells from the peripheral blood of seven previously untreated ET patients and one healthy adult. The mutational profiles in these patients were as follows: JAK2 V617F in two, CALR in three (one type I and two type II) and triple‐negative (TN) in two. Our results reveal substantial heterogeneity within this enrolled cohort of patients. Activation of JAK/STAT signalling was recognized in discrepant progenitor lineages among different samples. Significantly disparate molecular profiling was identified in the comparison between ET patients and the control, between patients with different driver mutations (JAK2 V617F and CALR exon 9 indel), and even between patients harbouring the same driver. Intra‐individual clonal diversity was also found in the CD34+ progenitor population of a patient, possibly indicating the presence of multiple clones in this case. Estimation of subpopulation size based on cellular immunophenotyping suggested differentiation bias in all analysed samples. Furthermore, combining the transcriptomic information with data from targeted sequencing enabled us to unravel key somatic mutations that are molecularly relevant. To conclude, we demonstrated that scRNA‐Seq extended our knowledge of clonal diversity and inter‐individual heterogeneity in patients with ET. The obtained information could potentially leapfrog our efforts in the elucidation of the pathogenesis of the disease.

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Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies

Cited by 125 publications

References 90 publications

Emerging treatments for classical myeloproliferative neoplasms

Emerging treatments for classical myeloproliferative neoplasms

Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients

Molecular heterogeneity unravelled by single‐cell transcriptomics in patients with essential thrombocythaemia

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