Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia

Bellon, Marcia; Lü, Ling; Nicot, Christophe

doi:10.1182/blood-2015-11-685032

Cited by 45 publications

(42 citation statements)

References 40 publications

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“…In contrast, Pim‐1 and Pim‐2 were expressed in all T‐cell lines irrespective of HTLV‐1 infection. Consistent with our results, it has recently been reported that Pim‐1 is constitutively expressed in HTLV‐1–infected T‐cell lines and ATL cells . Tax contributes to the survival of HTLV‐1–infected T cells by activating factors such as NF‐κB and AP‐1 .…”

Section: Discussionsupporting

confidence: 92%

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Expression and significance of Pim‐3 kinase in adult T‐cell leukemia

Ishikawa

Senba

Hashimoto³

et al. 2017

European J of Haematology

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Section: Discussionsupporting

confidence: 92%

“…The serine/threonine Pim protein kinase is overexpressed in many hematopoietic malignancies . The Pim family is composed of three members, Pim‐1, ‐2, and ‐3.…”

Section: Introductionmentioning

confidence: 99%

Expression and significance of Pim‐3 kinase in adult T‐cell leukemia

Ishikawa

Senba

Hashimoto³

et al. 2017

European J of Haematology

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“…In a recent study by Kataoka et al (23), 81 ATL samples were analyzed by exome sequencing and the rate of mutation for FBXW7 was found to be much lower than in our study. However, using the same patient cohort we used in this study, we recently found a similar rate of mutation for STAT3 (25.5% in Caribbean vs. 21% for Japanese samples) (23,24). Therefore, we believe the rate of mutation may be higher for FBXW7 in the Caribbean population.…”

Section: Discussionmentioning

confidence: 50%

Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients

Yeh

Bellon

Pancewicz-Wojtkiewicz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Human T-cell leukemia virus type 1 (HTLV-I) is associated with adult T-cell leukemia (ATL), an aggressive lymphoproliferative disease with a dismal prognosis. We have previously described the presence of Notch1 activating mutations and constitutive Notch1 signaling in patients with acute ATL. In this study, we report a high frequency of F-box and WD repeat domain containing 7 (FBXW7)/hCDC4 mutations within the WD40 substrate-binding domain in 8 of 32 acute ATL patients (25%). Functionally, ATL FBXW7 mutants lost their ability to interact with intracellular Notch (NICD), resulting in increased protein stability and constitutive Notch1 signaling. Consistent with the loss-of-function found in ATL patients, expression of WT FBXW7 in several patient-derived ATL lines demonstrated strong tumor-suppressor activity characterized by reduced proliferation of ATL cells. Remarkably, two FBXW7 mutants, D510E and D527G, demonstrated oncogenic activity when expressed in the presence of HTLV-I Tax, mutated p53 R276H, or c-Myc F138C found in human cancers. Transforming activity was further demonstrated by the ability of the FBXW7 D510E mutant to provide IL-2–independent growth of Tax-immortalized human T cells and increase the tumor formation in a xenograft mouse model of ATL. This study suggests that FBXW7, normally a tumor suppressor, can act as an oncogene when mutated and may play an important role in the pathogenesis of ATL.

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“…F1 mice by Pim-1 inhibition. We next treated (NZB × NZW) F1 mice with a Pim-1 inhibitor, AZD1208, which had demonstrated preclinical efficacy in several cancers (19,20,27,28). Proteinuria (according to the urinary albumin-to-creatinine ratio) was remarkably delayed in AZD1208-treated animals over the 12-week observation period (Figure 2A).…”

Section: Attenuation Of Lupus-like Syndrome In (Nzb × Nzw)mentioning

confidence: 99%

Pim‐1 as a Therapeutic Target in Lupus Nephritis

Xia

et al. 2019

Arthritis & Rheumatology

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Objective Lupus nephritis (LN) is a major determinant of morbidity and mortality in systemic lupus erythematosus (SLE). Pim‐1 regulates lymphocyte proliferation and activation. The role of Pim‐1 in autoimmune disease remains unclear. This study was undertaken to test the hypothesis that inhibition of Pim‐1 would have therapeutic potential in patients with LN. Methods Pim‐1 expression was analyzed in lupus‐prone (NZB × NZW)F1 mice (n = 6), human peripheral blood mononuclear cells (PBMCs) from SLE patients (n = 10), and glomeruli from patients with LN (n = 8). The therapeutic effect of the Pim‐1 inhibitor AZD1208 was assessed in the same murine lupus model (n = 10 mice per group). In vitro analysis was conducted to explore the mechanisms of action of Pim‐1 in mouse and human podocytes after Pim‐1 expression had been induced by anti–double‐stranded DNA (anti‐dsDNA) antibody–positive serum. Finally, MRL/lpr mice were used to confirm the therapeutic effects of Pim‐1 inhibition in vivo (n = 10 mice per group). Results Up‐regulation of Pim‐1 was seen in renal lysates from diseased (NZB × NZW)F1 mice and in PBMCs from patients with SLE and renal biopsy tissue from patients with LN, relative to their control counterparts (each P < 0.05). The Pim‐1 inhibitor AZD1208 reduced the severity of proteinuria, glomerulonephritis, renal immune complex deposits, and serum anti‐dsDNA antibody levels, concomitant with the suppression of NFATc1 expression and NLRP3 inflammasome activation, in diseased (NZB × NZW)F1 mice (each P < 0.05 versus controls). Moreover, in mouse and human podocytes, Pim‐1 knockdown with targeted small interfering RNA (siRNA) suppressed NFATc1 and NLRP3 inflammasome signaling in the presence of anti‐dsDNA–positive serum (each P < 0.05 versus control siRNA). Mechanistically, Pim‐1 modulated NLRP3 inflammasome activation through intracellular Ca2+ (P < 0.05 versus normal controls). The therapeutic effect of Pim‐1 blockade was replicated in MRL/lpr mice. Conclusion These data identify Pim‐1 as a critical regulator of LN pathogenesis in patients with SLE. Targeting of the Pim‐1/NFATc1/NLRP3 pathway might therefore have therapeutic potential in human LN.

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Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia

Abstract: Key Points Epigenetic silencing of miR-124a leads to constitutive STAT3 and activation of downstream Pim1. Pim1 kinase signaling is constitutively activated in ATL cells and represents a novel therapeutic target.

Cited by 45 publications

References 40 publications

Expression and significance of Pim‐3 kinase in adult T‐cell leukemia

Expression and significance of Pim‐3 kinase in adult T‐cell leukemia

Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients

Pim‐1 as a Therapeutic Target in Lupus Nephritis

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