The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2V617F myeloproliferative neoplasm cells

Calzada, Ariel Amaru; Todoerti, Katia; Donadoni, Luca; Pellicioli, Anna; Tuana, Giacomo; Gatta, Raffaella; Neri, Antonino; Finazzi, Guido; Mantovani, Roberto; Introna, Martino; Lombardi, Luigia; Golay, Joseé

doi:10.1016/j.exphem.2012.04.007

Cited by 38 publications

(27 citation statements)

References 47 publications

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“…However, CNA are potentially highly informative concerning targeted therapies (24). In particular, FGFR1 (8p12) and MYB (6q22-q23), found here in peak regions of gain, are targetable: MYB could be targeted by several drugs under development (25,26), and FGFR1 amplified NSCLCs have been shown to be sensitive to FGFR1 inhibitors (27)(28).…”

Section: Discussionmentioning

confidence: 94%

Lung Squamous Cell Carcinomas with Basaloid Histology Represent a Specific Molecular Entity

Brambilla

Laffaire

Lantuéjoul

et al. 2014

Clinical Cancer Research

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Purpose: The basaloid carcinoma (pure) and the (mixed) basaloid variant of lung squamous cell carcinoma (SCC) have a dismal prognosis but their underlying specific molecular characteristics remain obscure and no therapy has proven to be efficient.Experimental Design: To assess their molecular specificity among other lung SCCs we analyzed DNA copy number aberrations and mRNA expression pangenomic profiles of 93 SCCs, including 42 basaloid samples (24 pure, 18 mixed).Results: Supervised analyses reveal that pure basaloid tumors display a specific mRNA expression profile, encoding factors controlling the cell cycle, transcription, chromatin, and splicing, with prevalent expression in germline and stem cells, while genes related to squamous differentiation are underexpressed. From this signature, we derived a 2-genes (SOX4, IVL) immunohistochemistry-based predictor that discriminated basaloid tumors (pure and mixed) from non-basaloid tumors with 94% accuracy in an independent series. The pure basaloid tumors are also distinguished through unsupervised analyses. Using a centroid-based predictor, the corresponding molecular subtype was found in 8 independent public datasets (n ¼ 58/533), and was shown to be associated with a very poor survival as compared with other SCCs (adjusted HR ¼ 2.45; P ¼ 0.000001).Conclusion: This study enlightens the heterogeneity of SCCs that can be subclassified in mRNA expression subtypes. This study demonstrates for the first time that basaloid SCCs constitute a distinct histomolecular entity, which justifies its recognition and distinction from non-basaloid SCCs. In addition, their characteristic molecular profile highlights their intrinsic resistance to cytotoxic chemotherapy and could serve as a guide for targeted therapies. Clin Cancer Res; 20(22); 5777-86. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 94%

Lung Squamous Cell Carcinomas with Basaloid Histology Represent a Specific Molecular Entity

Brambilla

Laffaire

Lantuéjoul

et al. 2014

Clinical Cancer Research

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“…The specificity of GVS appears to be due to its ability to inhibit JAK2 V617F and downstream STAT5/STAT3 phosphorylation [12,19]. More recent studies indicate that GVS acts through modulation of both JAK-STAT-dependent and independent genes [13]. On the basis of these in vitro data, the drug has been tested recently in a pilot clinical study for JAK2 V617F -positive MPNs as a single treatment [10].…”

Section: Discussionmentioning

confidence: 96%

“…The drug downmodulates phosphorylated JAK2 and downstream STAT5/STAT3 [12] and therefore affects genes targeted by this pathway. It also modulates genes involved in hematopoietic differentiation through direct effects on histone modifications [13]. One of the common biological effects of HDAC inhibitors in different cellular contexts is to induce p21CDKN1A (WAF1/CIP1) expression in a p53-independent manner, therefore leading to cell cycle arrest in the G1 phase [14][15][16][17].…”

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confidence: 99%

Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2V617F myeloproliferative neoplasm patients

Calzada

Pedrini

Finazzi

et al. 2013

Experimental Hematology

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“…An investigation using givinostat showed JAK2V617F 1 cells to be 2-3 times more sensitive to givinostat-induced inhibition of colony formation, cellular proliferation, and apoptosis induction than JAK2-wild type cells. 57 HDAC inhibitors are currently under clinical investigation with ruxolitinib (www.ClinicalTrials.gov identifier #NCT01693601 in the United States and www.ClinicalTrials. gov identifier #NCT01433445 in the United Kingdom).…”

Section: Org Frommentioning

confidence: 99%

Therapy for myeloproliferative neoplasms: when, which agent, and how?

Geyer¹,

Mesa

2014

Blood

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Myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis (MF) (both primary and secondary), are recognized for their burdensome symptom profiles, life-threatening complications, and risk of progression to acute leukemia. Recent advancements in our ability to diagnose and prognosticate these clonal malignancies have paralleled the development of MPN-targeted therapies that have had a significant impact on disease burden and quality of life. Ruxolitinib has shown success in alleviating the symptomatic burden, reducing splenomegaly and improving quality of life in patients with MF. The role and clinical expectations of JAK2 inhibition continues to expand to a variety of investigational arenas. Clinical trials for patients with MF focus on new JAK inhibitors with potentially less myelosuppression (pacritinib) or even activity for anemia (momelotinib). Further efforts focus on combination trials (including a JAK inhibitor base) or targeting new pathways (ie, telomerase). Similarly, therapy for PV continues to evolve with phase 3 trials investigating optimal frontline therapy (hydroxyurea or IFN) and second-line therapy for hydroxyurea-refractory or intolerant PV with JAK inhibitors. In this chapter, we review the evolving data and role of JAK inhibition (alone or in combination) in the management of patients with MPNs.

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The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2V617F myeloproliferative neoplasm cells

Cited by 38 publications

References 47 publications

Lung Squamous Cell Carcinomas with Basaloid Histology Represent a Specific Molecular Entity

Lung Squamous Cell Carcinomas with Basaloid Histology Represent a Specific Molecular Entity

Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2V617F myeloproliferative neoplasm patients

Therapy for myeloproliferative neoplasms: when, which agent, and how?

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