PPARγ agonists promote the resolution of myelofibrosis in preclinical models

Lambert, Juliette; Calderón, Carolina; Sii-Felice, Karine; Salma, Mohammad; Edmond, Valérie; Alvarez, Jean‐Claude; Delord, Marc; Marty, Caroline; Plo, Isabelle; Kiladjian, Jean‐Jacques; Soler, Éric; Vainchenker, William; Villeval, Jean-Luc; Rousselot, Philippe; Prost, Stéphane

doi:10.1172/jci136713

Cited by 6 publications

(3 citation statements)

References 75 publications

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“…Interestingly, PPARD has been demonstrated to be upregulated in ET patients [34]. In the case of PPARG, it has been extensively linked to MPNs, since its ligands promote the resolution of myelofibrosis in preclinical models [35] and seem to be crucial for the development of new therapeutic approaches for hematological malignancies [36].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis Reveals JAK2/MPL-Independent Effects of Calreticulin Mutations in a C. elegans Model

Guijarro-Hernández

Eder-Azanza

Hurtado

et al. 2023

Cells

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There is growing evidence that Ph-negative myeloproliferative neoplasms (MPNs) are disorders in which multiple molecular mechanisms are significantly disturbed. Since their discovery, CALR driver mutations have been demonstrated to trigger pathogenic mechanisms apart from the well-documented activation of JAK2/MPL-related pathways, but the lack of experimental models harboring CALR mutations in a JAK2/MPL knockout background has hindered the research on these non-canonical mechanisms. In this study, CRISPR/Cas9 was performed to introduce homozygous patient-like calreticulin mutations in a C. elegans model that naturally lacks JAK2 and MPL orthologs. Whole-genome transcriptomic analysis of these worms was conducted, and some of the genes identified to be associated with processes involved in the pathogenesis of MPNs were further validated by qPCR. Some of the transcriptomic alterations corresponded to typically altered genes and processes in cancer and Ph-negative MPN patients that are known to be triggered by mutant calreticulin without the intervention of JAK2/MPL. However, interestingly, we have also found altered other processes described in these diseases that had not been directly attributed to calreticulin mutations without the intervention of JAK2 or MPL. Thus, these results point to a new experimental model for the study of the JAK2/MPL-independent mechanisms of mutant calreticulin that induce these biological alterations, which could be useful to study unknown non-canonical effects of the mutant protein. The comparison with a calreticulin null strain revealed that the alteration of all of these processes seems to be a consequence of a loss of function of mutant calreticulin in the worm, except for the dysregulation of Hedgehog signaling and flh-3. Further analysis of this model could help to delineate these mechanisms, and the verification of these results in mammalian models may unravel new potential therapeutic targets in MPNs. As far as we know, this is the first time that a C. elegans strain with patient-like mutations is proposed as a potential model for leukemia research.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis Reveals JAK2/MPL-Independent Effects of Calreticulin Mutations in a C. elegans Model

Guijarro-Hernández

Eder-Azanza

Hurtado

et al. 2023

Cells

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“…Peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator of gene expression, is reduced in various fibrotic and inflammatory disorders [78,79]. Treatment with PPARγ agonists, such as Pioglitazone and Mesalazine, counteracted myeloproliferation, Mk hyperplasia, spleen size in TPO high , JAK2 V617F , and CALR del52 mice [80]. PPARγ agonists also reduce MF through TGF-β1-dependent signaling mechanisms in BM stromal cells.…”

Section: Dysregulated Molecular and Transcriptional Network In Myelof...mentioning

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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“…More recent observations in MF include identification of STK11 as a tumor suppressor and that loss of LKB1/STK11 leads to stabilization of HIF1α and thus might promote disease progression ( 68 ), impaired megakaryocyte maturation associated with reduced GATA1 expression that might stem from ribosomal deficiency ( 69 ), and identification of aurora kinase A ( 70, 71 ), peroxisome proliferator-activated receptor gamma (PPARγ; ref. 72 ) and cyclin-dependent kinase 6 (CDK6; ref. 73 ), as therapeutic targets in MF.…”

Section: Pathogenetic Insightsmentioning

confidence: 99%

Myelofibrosis: Genetic Characteristics and the Emerging Therapeutic Landscape

et al. 2022

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Primary myelofibrosis (PMF) is one of three myeloproliferative neoplasms (MPN) that are morphologically and molecularly inter-related, the other two being polycythemia vera (PV) and essential thrombocythemia (ET).MPNs are characterized by JAK-STAT activating JAK2, CALR or MPL mutations that give rise to stem cellderived clonal myeloproliferation, which is prone to leukemic and, in case of PV and ET, fibrotic transformation. Abnormal megakaryocyte proliferation is accompanied by bone marrow fibrosis and characterizes PMF, while the clinical phenotype is pathogenetically linked to ineffective hematopoiesis and aberrant cytokine expression. Among MPN-associated driver mutations, type 1-like CALR mutation has been associated with favorable prognosis in PMF, while ASXL1, SRSF2, U2AF1-Q157, EZH2, CBL and K/NRAS mutations have been shown to be prognostically detrimental. Such information has enabled development of exclusively genetic (GIPSS) and clinically integrated (MIPSSv2) prognostic models that facilitate individualized treatment decisions. Allogeneic stem cell transplantation remains the only treatment modality in MF with the potential to prolong survival, whereas drug therapy, including JAK2 inhibitors, is directed mostly at the inflammatory component of the disease and is therefore palliative in nature. Similarly, disease-modifying activity remains elusive for currently available investigational drugs while their additional value in symptom management awaits controlled confirmation. There is a need for genetic characterization of clinical observations followed by in vitro and in vivo preclinical studies that will hopefully identify therapies that target the malignant clone in MF to improve patient outcomes.Research.

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PPARγ agonists promote the resolution of myelofibrosis in preclinical models

Cited by 6 publications

References 75 publications

Transcriptomic Analysis Reveals JAK2/MPL-Independent Effects of Calreticulin Mutations in a C. elegans Model

Transcriptomic Analysis Reveals JAK2/MPL-Independent Effects of Calreticulin Mutations in a C. elegans Model

Inflammation and bone marrow fibrosis: novel immunotherapeutic targets

Myelofibrosis: Genetic Characteristics and the Emerging Therapeutic Landscape

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