Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias

Kucine, Nicole; Marubayashi, Sachie; Bhagwat, Neha; Papalexi, Efthymia; Koppikar, Priya; Martin, Marta Sanchez; Dong, Lauren; Tallman, Marty S.; Paietta, Elisabeth; Wang, Kai; He, Jie; Lipson, Doron; Stephens, Phil; Miller, V. A.; Rowe, Jacob M.; Teruya‐Feldstein, Julie; Mullighan, Charles G.; Ferrando, Adolfo A.; Krivtsov, Andrei V.; Armstrong, Scott A.; Leung, Laura; Ochiana, Stefan O.; Chiosis, Gabriela; Levine, Ross L.; Kleppe, Maria

doi:10.1182/blood-2015-03-635821

Cited by 35 publications

(21 citation statements)

References 18 publications

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“…To translate the effects of Hsp90 deficiency in vitro into an in vivo setting, we assessed leukemia burden in T-ALL xenograftbearing mice with or without PU-H71, which had shown great efficacies in various preclinical tumor models (15,(34)(35)(36), and is currently under clinical examination (27). For this, CUTLL1 cells were intravenously injected into immunodeficient NSI mice.…”

Section: Hsp90 Inhibition Induces T-all Cell Apoptosis In Vitro and Imentioning

confidence: 99%

“…After three weeks of treatment, mice were sacrificed and analyzed for T-ALL progression. including AKT (43), JAK (36), and Tyk2 (44,45), also play important roles in T-ALL pathogenesis. By adding an important new member in this list, our data provide a rationale for immediate clinical development of Hsp90 inhibitors in treating T-ALL and other Notch1-addicted malignancies.…”

Section: Figurementioning

confidence: 99%

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Stabilization of Notch1 by the Hsp90 Chaperone is Crucial for T-Cell Leukemogenesis

Wang

Xiao

et al. 2017

Clinical Cancer Research

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Notch1 deregulation is assuming a focal role in T-cell acute lymphoblastic leukemia (T-ALL). Despite tremendous advances in our understanding of Notch1 transcriptional programs, the mechanisms by which Notch1 stability and turnover are regulated remain obscure. The goal of the current study is to identify intracellular Notch1 (ICN1, the activated form of Notch1) binding partner(s) regulating its stability and activity. We employed immunoaffinity purification to identify ICN1-associating partner(s) and used coimmunoprecipitation to verify the endogenous protein interaction. Pharmacologic or short hairpin RNA-mediated inhibition was applied in loss-of-function assays to assess the role of tentative binding partner(s) in modulating ICN1 protein stability as well as affecting T-ALL cell expansion and Mechanistic analysis involved protein degradation and polyubiquitination assays. We identify the Hsp90 chaperone as a direct ICN1-binding partner essential for its stabilization and transcriptional activity. T-ALL cells exhibit constitutive endogenous ICN1-Hsp90 interaction and Hsp90 depletion markedly decreases ICN1 levels. The Hsp90-associated E3 ubiquitin ligase Stub1 mediates the ensuring proteasome-dependent ICN1 degradation. Administration of 17-AAG or PU-H71, two distinct Hsp90 inhibitors, depletes ICN1, inhibits T-ALL cell proliferation, and triggers dramatic apoptotic cell death. Systemic treatment with PU-H71 reduces ICN1 expression and profoundly inhibits murine T-ALL allografts as well as human T-ALL xenografts. Our findings demonstrate Hsp90 blockade leads to ICN1 destabilization, providing an alternative strategy to antagonize oncogenic Notch1 signaling with Hsp90-selective inhibitors..

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Section: Hsp90 Inhibition Induces T-all Cell Apoptosis In Vitro and Imentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Stabilization of Notch1 by the Hsp90 Chaperone is Crucial for T-Cell Leukemogenesis

Wang

Xiao

et al. 2017

Clinical Cancer Research

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“…Research is currently ongoing for a better understanding of the genomics of this group and we now know that this group harbors certain targetable genetic alterations. Potential targets and agents tested in preclinical models include; CRLF2 inhibition (Givinostat [100], Luminespib [101], Selumetinib [102], TSLPR CART cells [103]), JAK-2 (CHZ868) [104], mTOR pathway (Rapamycin) [105], PI3K and mTOR pathways (Gedatolisib) [106], and TNF-a inhibition (Birinapant) [107]. These targets are now being prospectively studies in clinical trials across various centres.…”

Section: Philadelphia-like All (Ph-like All)mentioning

confidence: 99%

Pediatric Acute Lymphoblastic Leukemia: Recent Advances for a Promising Future

Tandon¹,

Punnett²

2019

Advances in Hematologic Malignancies

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Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and accounts for approximately 75% of all cases of childhood leukemia. Both diagnostic and therapeutic advances have been instrumental in improving the outcomes of once a dreaded disease. Currently, approximately 90% of the children treated according to risk-directed and response-adapted therapy will be long-term survivors. The use of pediatric protocols for the treatment of adolescent and young adults (AYA) has also resulted in significant improvements in their long-term survival. New therapies including tyrosine kinase inhibitors (TKIs), monoclonal antibodies and CAR T-cell therapy are changing the approach to therapy for relapsed or refractory disease. We are approaching a time where therapy for all patients will be personalized with the use of genome-based characterization of disease and incorporation of drugs against actionable targets, ultimately leading to improved clinical outcomes and decreased toxicity of therapy. Still, certain subgroups including patients with relapsed disease, infant ALL, and those with certain cytogenetic/molecular variants, remain challenging to treat. This chapter is an overview of the recent advances in the ALL disease biology, newly identified prognostic factors and an overview of emerging therapeutic options.

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“…İlk olarak, vahşi (wild) tip veya mutant JAK2'nin AUY922 veya PU-H71 tarafından yıkılmasını destekleyen ısı şok proteini 90'ın (HSP90) inhibisyonu; JAK inhibitörlerine duyarsızlaşan veya JAK inhibisyonu sonrası tedavi-dirençli kinaz domain mutasyonları gelişen, CRLF2 yeniden düzenlenmiş veya JAK-mutant ALL hücre dizilerinde ve mürin modellerinde, proliferasyon inhibisyonu ve sinyal yolaklarında baskılanma sağlamıştır (40,41). Ayrıca yakın zamanda IKZF1 ile mutasyona uğramış BCR-ABL1 hücre dizilerinde ve hastadan elde edilen ksenogreft modellerinde retinoidlerin preklinik etkinliği tanımlanmıştır (42).…”

Section: Abl1 Abl2 Csf1runclassified

Ph-like Acute Lymphoblastic Leukemia

Akay¹,

Ersoy²

2018

LLM Dergi

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Ph-like Acute Lymphoblastic Leukemia ÖZET Philadelphia (Ph)-benzer (veya BCR-ABL1-benzer) akut lenfoblastik lösemi (ALL), gen ekspresyon profili Ph-pozitif ALL ile benzer olan ancak BCR-ABL1 translokasyonu olmayan yeni bir ALL alt grubudur. Adolesan ve erişkinlerde daha sık izlenmekte olup 21-39 yaş genç erişkinlerin %27'sinde bildirilmiştir. Olumsuz klinik özellikler ve kötü prognoz ile karakterizedir. Sitokin reseptör genlerini ve kinaz sinyal yolaklarını aktive eden çok sayıda genetik değişikliklerin bu alt tipte bulunması, tedavide kişiye özel kinaz inhibitörlerini uygulanabilir hale getirmektedir. Halen devam etmekte olan çok sayıda klinik çalışmada, Ph-benzer ALL'li hastaların gen rearanjmanları açısından prospektif olarak taranması ve ABL-sınıf gen rearanjmanı veya JAK-STAT yolağını aktive eden mutasyonu olan hastaların tedavisine uygun tirozin kinaz inhibitörlerinin eklenmesi araştırılmaktadır.

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Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias

Abstract: Key Points PU-H71, a novel purine scaffold inhibitor, shows potent therapeutic efficacy in JAK-mutant ALL cells and mouse models. HSP90 inhibition retains therapeutic efficacy in ruxolitinib-persistent JAK-mutant ALL cells.

Cited by 35 publications

References 18 publications

Stabilization of Notch1 by the Hsp90 Chaperone is Crucial for T-Cell Leukemogenesis

Stabilization of Notch1 by the Hsp90 Chaperone is Crucial for T-Cell Leukemogenesis

Pediatric Acute Lymphoblastic Leukemia: Recent Advances for a Promising Future

Ph-like Acute Lymphoblastic Leukemia

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