Unraveling survivin expression in chronic myeloid leukemia: Molecular interactions and clinical implications

Bernardo, Paula Sabbo; Lemos, Lauana Greicy Tonon; Moraes, Gabriela Nestal de; Maia, Raquel Ciuvalschi

doi:10.1016/j.blre.2020.100671

Cited by 14 publications

(6 citation statements)

References 153 publications

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“…Along this line, the multiple functions of survivin have been closely tied to its subcellular localization. It is widely acknowledged that nuclear survivin is involved in mitosis, whereas cytoplasmic surviving is related to apoptosis [63]. The finding that overexpression of mutated Thr34-survivin failed to impact macrophage gene expression indicates that the role of survivin in macrophage plasticity may be dependent on its phosphorylation on Thr34, which is usually linked to its anti-apoptotic function [46,64,65].…”

Section: Discussionmentioning

confidence: 99%

Survivin drives tumor-associated macrophage reprogramming: a novel mechanism with potential impact for obesity

et al. 2021

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Purpose Recent studies point to adipose-derived stem cells (ASCs) as a link between obesity and cancer. We aimed to determine whether survivin, which is highly secreted by ASCs from subjects with obesity, might drive a pro-tumoral phenotype in macrophages. Methods The effect of ASC conditioned medium on the macrophage phenotype was assessed by expression studies. Survivin intracellular localization and internalization were examined by subcellular fractionation and immunofluorescence, respectively. Loss- and gain-of-function studies were performed using adenoviral vectors, and gene expression patterns, migration and invasion capacities of cancer cells were examined. Heterotypic cultures of ASCs, macrophages and cancer cells were established to mimic the tumor microenvironment. Survivin-blocking experiments were used to determine the impact of survivin on both macrophages and cancer cells. Immunohistochemical analysis of survivin was performed in macrophages from ascitic fluids of cancer patients and healthy controls. Results We found that obese-derived ASCs induced a phenotypic switch in macrophages characterized by the expression of both pro- and anti-inflammatory markers. Macrophages were found to internalize extracellular survivin, generating hybrid macrophages with a tumor-associated phenotype that included secretion of survivin. Exogenous expression of survivin in macrophages generated a similar phenotype and enhanced the malignant characteristics of cancer cells by a mechanism dependent on survivin phosphorylation at threonine 34. Survivin secreted by both ASCs from subjects with obesity and tumor-associated macrophages synergistically boosted the malignancy of cancer cells. Importantly, survivin was mainly detected in ascites-associated macrophages from patients with a malignant diagnosis. Conclusion Our data indicate that survivin may serve as a molecular link between obesity and cancer and as a novel marker for tumor-associated macrophages.

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Section: Discussionmentioning

confidence: 99%

Survivin drives tumor-associated macrophage reprogramming: a novel mechanism with potential impact for obesity

et al. 2021

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“…Furthermore, CML patients resistant to TKIs and Imatinib-resistant cell lines show higher survivin levels than the sensitive ones [ 127 ]. Survivin is an inhibitor of apoptosis protein (IAP), downstream of the BCR-ABL1 signaling pathway, known to regulate the cell cycle and apoptosis, favoring the survival of cancer cells by evading cell death and promoting cell division [ 128 ]. Zhou et al showed that a combination treatment of a WNT/β-catenin signaling inhibitor with Nilotinib synergistically killed KBM5 T315I cells (a CML resistant cell line) as well as primary BC-CML cells obtained from TKI-resistant patients (with and without BCR-ABL1 kinase mutations) by decreasing the expression of CD44, MYC, p-CRKL, p-STAT5, and survivin [ 129 ].…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

Cancers

101

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Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

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“…Furthermore, we demonstrated increased sensitivity of p190 cells to two classes of apoptotic modulators, IAP inhibitors, and P53 modulators/MDM2 antagonists. IAP inhibitors/ SMAC mimetic drugs (ex: LCL161) target the antiapoptotic IAP molecules including cIAP1, cIAP2, and survivin and have shown potential activity in CML as a monotherapy and in combination with TKI [47][48][49]. Interestingly, p190 has been shown to cooperate with Src activation to drive γcatenin/MYC-induced survivin overexpression [50], which may partly explain enhanced sensitivity of p190 cells to IAP inhibitors over p210.…”

Section: Discussionmentioning

confidence: 99%

Characterization of p190-Bcr-Abl chronic myeloid leukemia reveals specific signaling pathways and therapeutic targets

et al. 2020

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The oncogenic protein Bcr-Abl has two major isoforms, p190Bcr-Abl and p210Bcr-Abl. While p210Bcr-Abl is the hallmark of chronic myeloid leukemia (CML), p190Bcr-Abl occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients. In CML, p190Bcr-Abl occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190Bcr-Abl and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190Bcr-Abl in CML and hematopoietic progenitor cell line models (Ba/f3 and HPC-LSK). p190Bcr-Abl CML patients demonstrated poor response to imatinib and frequent mutations in epigenetic modifiers genes. In contrast with p210Bcr-Abl, p190Bcr-Abl exhibited specific transcriptional upregulation of interferon, interleukin-1 receptor, and P53 signaling pathways, associated with hyperphosphorylation of relevant signaling molecules including JAK1/STAT1 and PAK1 in addition to Src hyperphosphorylation. Comparable to p190Bcr-Abl CML patients, p190Bcr-Abl cell lines demonstrated similar transcriptional and phospho-signaling signatures. With the drug sensitivity screening we identified targeted drugs with specific activity in p190Bcr-Abl cell lines including IAP-, PAK1-, and Src inhibitors and glucocorticoids. Our results provide novel insights into the mechanisms underlying the distinct features of p190Bcr-Abl CML and promising therapeutic targets for this high-risk patient group.

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Unraveling survivin expression in chronic myeloid leukemia: Molecular interactions and clinical implications

Cited by 14 publications

References 153 publications

Survivin drives tumor-associated macrophage reprogramming: a novel mechanism with potential impact for obesity

Survivin drives tumor-associated macrophage reprogramming: a novel mechanism with potential impact for obesity

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Characterization of p190-Bcr-Abl chronic myeloid leukemia reveals specific signaling pathways and therapeutic targets

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