Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

Ng, Samuel Y.; Yoshida, Noriaki; Christie, Amanda L.; Ghandi, Mahmoud; Dharia, Neekesh V.; Dempster, Joshua; Murakami, Mark A.; Shigemori, Kay; Morrow, Sara; Scoyk, Alexandria Van; Cordero, Nicolas A.; Stevenson, Kristen E.; Puligandla, Mäneka; Haas, Brian J.; Lo, Christopher; Meyers, Robin M.; Gao, Galen F.; Cherniack, Andrew D.; Louissaint, Abner; Nardi, Valentina; Thorner, Aaron R.; Long, Henry W.; Qiu, Xintao; Morgan, Elizabeth A.; Dorfman, David M.; Fiore, Danilo; Jang, Julie K.; Epstein, Alan L.; Doğan, Ahmet; Zhang, Yanming; Horwitz, Steven M.; Jacobsen, Eric; Santiago, Solimar; Ren, Jian-Guo; Guerlavais, Vincent; Annis, D. Allen; Aivado, Manuel; Saleh, Mansoor N.; Mehta, Amitkumar; Tsherniak, Aviad; Root, David E.; Vázquez, Francisca; Hahn, William C.; Inghirami, Giorgio; Aster, Jon C.; Weinstock, David M.; Koch, Raphael

doi:10.1038/s41467-018-04356-9

Cited by 85 publications

(77 citation statements)

References 69 publications

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“…39,53 In the presence of IL-2, cS5A hi mice-derived CTL cells were treated with increasing concentrations of these JAK and STAT5 inhibitors, leading to decreased STAT5 activation and cell viability ( Figure 7C Figure S7D). When we used Ruxolitinib we found that Mac1-and Mac2A cells that harbor a JAK2-translocation were sensitive 54 . Control cell lines were only affected 17 / 28 at significantly higher concentrations (AC-3-19: <20 µM, Online Supplementary Figure S7D, summary on mutations in human cells in Online Supplementary Table S7).…”

Section: Proliferation Of Ptcl Cells Is Highly Sensitive To Targetedmentioning

confidence: 98%

“…In CTCL, overexpression of oncogenic miR-155, 49 54,70 , and ATLL 71 revealed reduced proliferation and immunomodulatory effects on the PTCL tumor microenvironment. 3 Moreover, a small molecule inhibitor of STAT5 SH 2 domain-phosphopeptide interactions 39 resulted in strongly reduced viability in PTCL lines with high STAT5 activity and its successor compound showed significant effects in AML.…”

Section: Proliferation Of Ptcl Cells Is Highly Sensitive To Targetedmentioning

confidence: 99%

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High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

et al. 2019

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Section: Proliferation Of Ptcl Cells Is Highly Sensitive To Targetedmentioning

confidence: 98%

Section: Proliferation Of Ptcl Cells Is Highly Sensitive To Targetedmentioning

confidence: 99%

High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

et al. 2019

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“…These findings support the notion that the serial transplantation of PDX models may enhance drug sensitivity, which in turn may contribute to the observations of variable clinical responses. Because of proven discrepancies in drug sensitivity in later passage PDXs, subsequent studies have modified the experimental design to use early passage PDX models . A recent study in head and neck squamous cell carcinoma showed genomic SMAD family member 4 (SMAD4) alterations in PDX .…”

Section: Aggressive Phenotypes and Variable Drug Sensitivitymentioning

confidence: 99%

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Shi

Jia

et al. 2019

Intl Journal of Cancer

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Patient‐derived xenograft (PDX) models are widely used as preclinical cancer models and are considered better than cell culture models in recapitulating the histological features, molecular characteristics and intratumoral heterogeneity (ITH) of human tumors. While the PDX model is commonly accepted for use in drug discovery and other translational studies, a growing body of evidence has suggested its limitations. Recently, the fidelity of cancer cells within a PDX has been questioned, which may impede the future application of these models. In this review, we will focus the variable phenotypes of xenograft tumors and the genomic instability and molecular inconsistency of PDX tumors after serial transplantation. Next, we will discuss the underlying mechanism of ITH and its clinical relevance. Stochastic selection bias in the sampling process and/or deterministic clonal dynamics due to murine selective pressure may have detrimental effects on the results of personalized medicine and drug screening studies. In addition, we aim to identify a possible solution for the issue of fidelity in current PDX models and to discuss emerging next‐generation preclinical models.

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“…In this context, patientderived xenograft models using human AITL cell lines with defined causative mutations may provide further insights. 56,57 In summary, our data suggest that ongoing T-B-cell cross talk is a driving force for the progression of Tfh-derived T-cell lymphomas. Importantly, this may apply not only to AITL but also to other peripheral T-cell lymphomas with features of Tfh origin.…”

Section: Discussionmentioning

confidence: 72%

Progression of AITL-like tumors in mice is driven by Tfh signature proteins and T-B cross talk

et al. 2020

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Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma driven by a pool of neoplastic cells originating from T follicular helper (Tfh) cells and concomitant expansion of B cells. Conventional chemotherapies for AITL have shown limited efficacy, and as such, there is a need for improved therapeutic options. Because AITL originates from Tfh cells, we hypothesized that AITL tumors continue to rely on essential Tfh components and intimate T-cell–B-cell (T-B) interactions. Using a spontaneous AITL mouse model (Roquinsan/+ mice), we found that acute loss of Bcl6 activity in growing tumors drastically reduced tumor size, demonstrating that AITL-like tumors critically depend on the Tfh lineage–defining transcription factor Bcl6. Because Bcl6 can upregulate expression of signaling lymphocytic activation molecule–associated protein (SAP), which is known to promote T-B conjugation, we next targeted the SAP-encoding Sh2d1a gene. We observed that Sh2d1a deletion from CD4+ T cells in fully developed tumors also led to tumor regression. Further, we provide evidence that tumor progression depends on T-B cross talk facilitated by SAP and high-affinity LFA-1. In our study, AITL-like tumors relied heavily on molecular pathways that support Tfh cell identity and T-B collaboration, revealing potential therapeutic targets for AITL.

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Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

Cited by 85 publications

References 69 publications

High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Progression of AITL-like tumors in mice is driven by Tfh signature proteins and T-B cross talk

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