Prevalent premalignancy

Sperling, Adam S.; Ebert, Benjamin L.

doi:10.1182/blood-2017-05-786210

Cited by 3 publications

(4 citation statements)

References 13 publications

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“…Early results from a completed single and multiple ascending dose clinical trials in healthy volunteers (NCT03046459 and NCT03239379) demonstrated that BNZ-1 was well tolerated with no major side effects. 39 Pharmacodynamic biomarkers showed high specificity to IL-2 and IL-15 (manuscript in preparation). These preclinical and early clinical successes indicate that BNZ-1 represents a promising therapeutic option for multiple disorders with dysregulated γc cytokines and abnormal activation of JAK/STAT pathways.…”

Section: Discussionmentioning

confidence: 99%

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IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability

et al. 2018

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Interleukin-15 (IL-15) and IL-2 drive T-cell malignancies including T-cell large granular lymphocyte leukemia (T-LGLL) and HTLV-1 driven adult T-cell leukemia (ATL). Both cytokines share common γ-chain receptors and downstream signaling pathways. T-LGLL is characterized by clonal expansion of cytotoxic T cells and is associated with abnormal JAK/STAT signaling. ATL is an aggressive CD4+ T cell neoplasm associated with HTLV-1. T-LGLL and ATL share dependence on IL-2 and IL-15 for survival and both diseases lack effective therapies. BNZ-1 is a pegylated peptide designed to specifically bind the γc receptor to selectively block IL-2, IL-15 and IL-9 signaling. We hypothesized that treatment with BNZ-1 would reduce cytokine mediated proliferation and viability. Our results demonstrated that in vitro treatment of a T-LGLL cell line and ex vivo treatment of T-LGLL patient cells with BNZ-1 inhibited cytokine mediated viability. Furthermore, BNZ-1 blocked downstream signaling and increased apoptosis. These results were mirrored in an ATL cell line and in ex vivo ATL patient cells. Lastly, BNZ-1 drastically reduced leukemic burden in an IL-15-driven human ATL mouse xenograft model. Thus, BNZ-1 shows great promise as a novel therapy for T-LGLL, ATL and other IL-2 or IL-15 driven hematopoietic malignancies.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, a recent phase 1 clinical trial proved BNZ-1 to be well tolerated in healthy subjects. 39 These positive results prompted us to determine the efficacy and mechanism of BNZ-1 in LGLL and ATL.…”

Section: Introductionmentioning

confidence: 99%

IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability

et al. 2018

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“…The presence of these mutations can be associated with expansion of the mutant clone, a risk of progression to malignancy, and increased all-cause mortality. These MDS/AML-associated somatic mutations without cytopenia or dysplasia define the entity of clonal hematopoiesis of undetermined significance (CHIP) (Steensma et al, 2015;Sperling et al, 2017). While multiple human, murine, and chimeric modeling approaches have been used successfully to study AML, MDS and CHIP have been much more difficult to interrogate experimentally.…”

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confidence: 99%

“…The decrease in megakaryocyte and erythroid differentiation in low-risk MDS iPSC clones was particularly striking, modeling the prominent feature of anemia and thrombocytopenia of early/low-risk MDS. While several syngeneic mouse models exist for key pathways mutated in MDS (recently reviewed in Sperling et al, 2017), human MDS has been challenging to model experimentally. The iPSC approach now generates a renewable source of human cells that provide an in vitro model for CHIP and MDS.…”

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confidence: 99%

Bridging the Gaps: iPSC-Based Models from CHIP to MDS to AML

Bernt

2017

Cell Stem Cell

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Myeloid malignancies exist on a spectrum from asymptomatic clonal hematopoiesis to overt leukemia and exhibit substantial clonal heterogeneity. Both aspects are challenging to capture in experimental models. In two landmark studies in this issue of Cell Stem Cell, Kotini et al. (2017) and Chao et al. (2017) establish iPSC-based experimental platforms that recapitulate disease stages and clonal architecture.

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Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia

Moignet

Lamy

2018

American Society of Clinical Oncology Educational Book

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Large granular lymphocyte (LGL) leukemia has been recognized in the World Health Organization classifications among mature T cell and natural killer cell neoplasms and is divided into three categories. Chronic T cell leukemia and natural killer cell lymphocytosis can be considered as a similar spectrum of an indolent disease characterized by cytopenias and autoimmune conditions. The last category, aggressive natural killer cell LGL leukemia is very rare, related to Epstein-Barr virus, and seen mainly in young Asian people. Clonal LGL expansion arises from chronic antigenic stimulation sustained by interleukin-15 and platelet-derived growth factor cytokine signal. Those leukemic cells are resistant to apoptosis, mainly because of constitutive activation of survival pathways including Jak/Stat, MapK, Pi3k-Akt, RasRaf-1, MEK1/ERK, sphingolipid, and NFκB. Stat3 constitutive activation is the hallmark of this lymphoproliferative disorder. Socs3 is downregulated, but no mutation could be found to explain this status. However, several somatic mutations, including Stat3, Stat5b, and tumor necrosis factor alpha-induced protein 3, have been demonstrated recently in LGL leukemia; they are identified in half of patients and cannot explain by themselves LGL leukemogenesis. Recurrent infections as a result of chronic neutropenia, anemia, and autoimmune disorders are the main complications related to LGL leukemia. Despite an indolent presentation, 10% of patients die, mainly because of infectious complications. Current treatments are based on immunosuppressive therapies. A better mechanistic understanding of LGL leukemia will allow future consideration of a personalized therapeutic approach perhaps based on Jak/Stat inhibitors, which may offer better results than current immunosuppressive therapy.

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Prevalent premalignancy

Cited by 3 publications

References 13 publications

IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability

IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability

Bridging the Gaps: iPSC-Based Models from CHIP to MDS to AML

Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia

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