Targeting the JAK-STAT pathway in lymphoma: a focus on pacritinib

Derenzini, Enrico; Younes, Anas

doi:10.1517/13543784.2013.775244

Cited by 34 publications

(32 citation statements)

References 90 publications

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“…There has been interest in employing JAK2 inhibitors in DLBCL (48,49), but the place of these agents has not been defined. We suggest that they might be useful adjuncts to conventional treatment in cases of ABC-DLBCL expressing relatively low levels of BCL6 and that BCL6 mRNA expression might be a component of a biomarker panel to predict patient populations that will benefit from these drugs.…”

Section: Bcl6 Bcormentioning

confidence: 99%

Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma

Beck

Zobel

Barber

et al. 2016

Journal of Biological Chemistry

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We demonstrate the usefulness of synthetic lethal screening of a conditionally BCL6-deficient Burkitt lymphoma cell line, DG75-AB7, with a library of small molecules to determine survival pathways suppressed by BCL6 and suggest mechanismbased treatments for lymphoma. Lestaurtinib, a JAK2 inhibitor and one of the hits from the screen, repressed survival of BCL6-deficient cells in vitro and reduced growth and proliferation of xenografts in vivo. BCL6 deficiency in DG75-AB7 induced JAK2 mRNA and protein expression and STAT3 phosphorylation. Surface IL10RA was elevated by BCL6 deficiency, and blockade of IL10RA repressed STAT3 phosphorylation. Therefore, we define an IL10RA/JAK2/STAT3 pathway each component of which is repressed by BCL6. We also show for the first time that JAK2 is a direct BCL6 target gene; BCL6 bound to the JAK2 promoter in vitro and was enriched by ChIP-seq. The place of JAK2 inhibitors in the treatment of diffuse large B-cell lymphoma has not been defined; we suggest that JAK2 inhibitors might be most effective in poor prognosis ABC-DLBCL, which shows higher levels of IL10RA, JAK2, and STAT3 but lower levels of BCL6 than GC-DLBCL and might be usefully combined with novel approaches such as inhibition of IL10RA.There is a need for new treatments for poor-prognosis activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), 6 which continues to have a cure rate Ͻ40% with conventional chemotherapy (1).The majority of ABC-DLBCL, in contrast to germinal center B-cell-like DLBCL, have low level expression of BCL6 mRNA and protein (2). JAK/STAT3 signaling is active in ABC-DLBCL and is enhanced by constitutive activity of the NF-B pathway (3), which in turn is driven by oncogenic CARD11 mutations (4), chronic active B-cell receptor signaling (5), and MYD88 mutations (6). However, other factors are also likely to be important in determining the overall activity of JAK/STAT3 signaling. BCL6 directly represses both STAT3 (7) and NF-B p105/p50 (8) transcription, and levels of BCL6 might, therefore, be a factor independent of the known oncogenic mutations, which determines the activity of signaling pathways required by ABC-DLBCL. In this report we develop a novel B-cell line to pursue the hypothesis that genes repressed by BCL6 are components of survival signaling pathways in lymphomas with low level expression of this transcription factor.BCL6 is a zinc finger transcription factor that is highly expressed in normal germinal center B-cells (9) and is required for high affinity antibody production (10, 11). It is also constitutively expressed in ϳ40% of cases of the high grade B-cell lymphoma DLBCL due to either chromosomal translocations, mutations of a negative regulatory site in the promoter region (12-14), or abnormalities of post-translational regulation (15)(16)(17).The N-terminal POZ domain of BCL6 associates with co-repressors NCOR1, BCOR, and SMRT (NCOR2), which in turn recruit histone deacetylases to accomplish transcriptional repression. Work largely carried out with human Burkitt lymphoma cel...

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Section: Bcl6 Bcormentioning

confidence: 99%

Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma

Beck

Zobel

Barber

et al. 2016

Journal of Biological Chemistry

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“…7 Recent studies highlight the importance of the JAK/STAT pathway for mechanisms of immune escape in lymphoma 8 and it has been shown to be involved in regulating programmed cell death in a variety of tumor types, including Hodgkin lymphoma (HL), and PMBCL.…”

Section: A B Cmentioning

confidence: 99%

A unique case of refractory primary mediastinal B-cell lymphoma with JAK3 mutation and the role for targeted therapy

et al. 2014

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“…This was generally the case for all macrocycles with pyridine or 5-membered A-rings. Compound 83, the thiophene analog of 2, had a 7 nM JAK2 IC 50 and improved selectivity profile compared to 1, but this came at the cost of decreased solubility. Furan 84 had a profile similar to 2 and was more than 100-fold selective for JAK2 over JAK3.…”

Section: Sar and Structural Biologymentioning

confidence: 99%

Designed Macrocyclic Kinase Inhibitors

Poulsen

William

Dymock

2014

Macrocycles in Drug Discovery

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Cancer continues to present as an increasing and serious global unmet medical need in today's aging population.1 Macrocyclic kinase inhibitors have reached advanced clinical testing and are making an impact in oncologic conditions including myelofibrosis, lymphomas and leukemias. Rheumatoid arthritis (RA) is also beginning to be impacted with the first macrocycle having entered Phase I clinical evaluation in healthy volunteers. Increasing reports of innovative macrocycles in preclinical research are appearing in the literature. Desirable, selective, multi-kinase inhibitory profiles against specific kinases known to be abrogated in cancer, RA, and other diseases have been achieved in a first generation series of clinical stage compact small molecule macrocyclic kinase inhibitors. Herein we discuss their design, synthesis, structure activity relationships and assessment of the latest clinical data in a range of oncologic conditions. Macrocyclic kinase inhibitors have the potential to offer new hope to patients and their families.

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Targeting the JAK-STAT pathway in lymphoma: a focus on pacritinib

Cited by 34 publications

References 90 publications

Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma

Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma

A unique case of refractory primary mediastinal B-cell lymphoma with JAK3 mutation and the role for targeted therapy

Designed Macrocyclic Kinase Inhibitors

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