Author: Liu, Liwei ; Luo, Wei ; Shalamu, Adilan ; Pei, Zhiqiang ; Weng, Xinyu ; Liu, Bowen ; Dong, Zhen ; Qu, Yanan ; Wei, Zilun ; Song, Shuai ; Ge, Junbo

Heart failure is the leading cardiovascular comorbidity in chronic kidney disease (CKD) patients. Among the types of heart failure according to ejection fraction, heart failure with preserved ejection fraction (HFpEF) is the most common type of heart failure in CKD patients. However, the specific animal model of HFpEF afer CKD is currently missing. In this study, we determined the heart failure characteristics and dynamic progression in CKD mice. Based on these features, we established the practical HFpEF after CKD mouse model using 5/6 subtotal nephrectomy and retinol administration. Active apoptosis, impaired calcium handling, an imbalance between eNOS and oxidative stress and engaged endoplasmic reticulum stress were observed in our model. RNSseq revealed distinct gene expression patterns between HFpEF after CKD and metabolic induced-HFpEF. Furthermore, we revealed the potential mechanism of the pro-HFpEF effect of retinol. Serum accumulation of retinol in CKD prompts myocardial hypertrophy and fibrosis by activating JAK2 and phosphorylating STAT5. Finally, using small molecule inhibitor AC-4-130, we found STAT5 phosphorylation inhibitor may be a potential intervention target for HFpEF after CKD. In conclusion, we provide a novel animal model and a potential drug target for HFpEF intervention in CKD.

01 May 2018·LeukemiaQ1 · MEDICINE

Pharmacologic inhibition of STAT5 in acute myeloid leukemia

Q1 · MEDICINE

Article

Author: Park, Jisung ; Wingelhofer, Bettina ; Tin, Gary ; Heyes, Elizabeth C ; Freund, Patricia ; Moriggl, Richard ; Keserű, György Miklós ; Grebien, Florian ; de Araujo, Elvin D ; Kubicek, Stefan ; Orlova, Anna ; Bajusz, Dávid ; Gunning, Patrick T ; Ahmar, Siawash ; Cumaraswamy, Abbarna A ; Berger-Becvar, Angelika ; Valent, Peter ; Maurer, Barbara ; Ruge, Frank ; Lardeau, Charles-Hugues ; Sadovnik, Irina

The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 is of significant clinical value. Here, we describe the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor, AC-4-130, which can efficiently block pathological levels of STAT5 activity in AML. AC-4-130 directly binds to STAT5 and disrupts STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription. Notably, AC-4-130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD⁺ AML patient cells in vitro and in vivo. Furthermore, AC-4-130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. Overall, the synergistic effects of AC-4-130 with TK inhibitors (TKIs) as well as emerging treatment strategies provide new therapeutic opportunities for leukemia and potentially other cancers.

Molecular Cancer

PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma

Article

Author: Abraham, B ; Edtmayer, S ; Klapper, W ; Look, T A ; Egger, G ; Timelthaler, G ; Pusch, O ; Högler, S ; Limberger, T ; Schmalzbauer, B S ; Anagnostopoulos, J ; Stoiber, D ; Lagger, S ; Giordano, C ; Schiefer, A I ; Kenner, L ; Zrimšek, M ; Schlederer, M ; Probst, C ; Kodajova, P ; Prutsch, N ; Moriggl, R ; Kornauth, C ; Staber, P B ; Wolf, P ; Kothmayer, M ; Woessmann, W ; Merkel, O ; Dey, S ; Zujo, L ; Gunning, P ; Zimmerman, M ; Mathas, S ; Wiest, I ; Tangermann, S ; Quintanilla-Martinez, L ; Kollmann, S ; Garces de Los Fayos Alonso, I ; Neubauer, H A ; Turner, S D

AbstractBackgroundAnaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive.Methods and resultsIn a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo.ConclusionsWe therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Preclinical	AT	University of Veterinary Medicine	02 Feb 2018
Acute Myeloid Leukemia	Preclinical	AT	Ludwig Boltzmann Institute	02 Feb 2018

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