A KLF4-DYRK2–mediated pathway regulating self-renewal in CML stem cells

Park, Chun Shik; Lewis, Andrew Henry; Chen, Taylor J; Bridges, Cory Seth; Ye, Shen; Suppipat, Koramit; Puppi, Monica; Tomolonis, Julie; Pang, Paul; Mistretta, Toni–Ann; Ma, Leyuan; Green, Michael R.; Rau, Rachel E.; Lacorazza, H. Daniel

doi:10.1182/blood.2018875922

Cited by 36 publications

(36 citation statements)

References 67 publications

(84 reference statements)

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“…A proper understanding of DYRK2 regulatory mechanisms would certainly help to clarify its role in diseases, especially in tumoral progression. At the transcriptional level, it has been described that KLF4 repressed DYRK2 gene expression in leukemic stem/progenitor cells [18]. Similarly, recent evidence shows that DNMT1 downregulates DYRK2 gene expression methylating its promoter, thereby increasing the proliferation of human colorectal cancer cells [19,20].…”

Section: Expression Regulation and Post-translational Modificationsmentioning

confidence: 95%

See 1 more Smart Citation

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Correa-Sáez

Jiménez‐Izquierdo

Garrido‐Rodríguez

et al. 2020

Cell. Mol. Life Sci.

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Members of the dual-specificity tyrosine-regulated kinase (DYRKs) subfamily possess a distinctive capacity to phosphorylate tyrosine, serine, and threonine residues. Among the DYRK class II members, DYRK2 is considered a unique protein due to its role in disease. According to the post-transcriptional and post-translational modifications, DYRK2 expression greatly differs among human tissues. Regarding its mechanism of action, this kinase performs direct phosphorylation on its substrates or acts as a priming kinase, enabling subsequent substrate phosphorylation by GSK3β. Moreover, DYRK2 acts as a scaffold for the EDVP E3 ligase complex during the G2/M phase of cell cycle. DYRK2 functions such as cell survival, cell development, cell differentiation, proteasome regulation, and microtubules were studied in complete detail in this review. We have also gathered available information from different bioinformatic resources to show DYRK2 interactome, normal and tumoral tissue expression, and recurrent cancer mutations. Then, here we present an innovative approach to clarify DYRK2 functionality and importance. DYRK2 roles in diseases have been studied in detail, highlighting this kinase as a key protein in cancer development. First, DYRK2 regulation of c-Jun, c-Myc, Rpt3, TERT, and katanin p60 reveals the implication of this kinase in cell-cycle-mediated cancer development. Additionally, depletion of this kinase correlated with reduced apoptosis, with consequences on cancer patient response to chemotherapy. Other functions like cancer stem cell formation and epithelial-mesenchymal transition regulation are also controlled by DYRK2. Furthermore, the pharmacological modulation of this protein by different inhibitors (harmine, curcumine, LDN192960, and ID-8) has enabled to clarify DYRK2 functionality.

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Section: Expression Regulation and Post-translational Modificationsmentioning

confidence: 95%

“…Likewise, further efforts have been done to elucidate DYRK2 role in chronic myeloid leukemia (CML) stem/progenitor cells. In 2019, Park et al demonstrated that SIAH2 ubiquitin E3 ligase inhibition using vitamin K3 produces the stabilization of DYRK2, which inhibits self-renewal via c-Myc depletion and p53 activation [18].…”

Section: Dyrk2 and Diseasementioning

confidence: 99%

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Correa-Sáez

Jiménez‐Izquierdo

Garrido‐Rodríguez

et al. 2020

Cell. Mol. Life Sci.

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“…Repression of DYRK2 expression has been associated with the progression of cancers such as hepatocellular carcinoma, gastric cancer, colorectal cancer, and breast cancer, and we studied this association in CML 14,[78][79][80][81] . Interestingly, genomic silencing of DYRK2 increased the ability of cells from pulmonary metastases of breast cancers to form mammospheres during serial passage, an assay of self-renewal capacity, and this effect was associated with elevated KLF4 levels; however, in this case, KLF4 expression was regulated by the androgen receptor through a pathogenic DYRK2-AR-KLF4 pathway, although the mechanism by which DYRK2 activated the androgen receptor was not identified 81 .…”

Section: Dyrk2mentioning

confidence: 99%

DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells

Park

Lacorazza

2020

Exp Mol Med

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Chronic myeloid leukemia is a hematological cancer driven by the oncoprotein BCR-ABL1, and lifelong treatment with tyrosine kinase inhibitors extends patient survival to nearly the life expectancy of the general population. Despite advances in the development of more potent tyrosine kinase inhibitors to induce a durable deep molecular response, more than half of patients relapse upon treatment discontinuation. This clinical finding supports the paradigm that leukemia stem cells feed the neoplasm, resist tyrosine kinase inhibition, and reactivate upon drug withdrawal depending on the fitness of the patient’s immune surveillance. This concept lends support to the idea that treatment-free remission is not achieved solely with tyrosine kinase inhibitors and that new molecular targets independent of BCR-ABL1 signaling are needed in order to develop adjuvant therapy to more efficiently eradicate the leukemia stem cell population responsible for chemoresistance and relapse. Future efforts must focus on the identification of new targets to support the discovery of potent and safe small molecules able to specifically eradicate the leukemic stem cell population. In this review, we briefly discuss molecular maintenance in leukemia stem cells in chronic myeloid leukemia and provide a more in-depth discussion of the dual-specificity kinase DYRK2, which has been identified as a novel actionable checkpoint in a critical leukemic network. DYRK2 controls the activation of p53 and proteasomal degradation of c-MYC, leading to impaired survival and self-renewal of leukemia stem cells; thus, pharmacological activation of DYRK2 as an adjuvant to standard therapy has the potential to induce treatment-free remission.

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“…We applied and tested the method using the signaling molecule and transcription factor KLF4, which is implicated in the stress-responsive regulation of cell cycle progression, apoptosis and differentiation as well as stemness and pluripotency [13][14][15][16][17][18][19]. KLF4 is downregulated in numerous cancers but upregulated in others, and abnormal KLF4 expression might reflect oncogenic or tumor suppressor functions depending on the cellular context, tumor type, subtype and stage [14,17,[20][21][22][23][24][25][26][27]. KLF4 is frequently deregulated in T-ALL and B-cell tumors [28][29][30][31][32][33][34], and is reportedly downregulated in pediatric B-ALL [35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Inducible transgene expression in PDX models in vivo identifies KLF4 as a therapeutic target for B-ALL

et al. 2020

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Background Clinically relevant methods are not available that prioritize and validate potential therapeutic targets for individual tumors, from the vast amount of tumor descriptive expression data. Methods We established inducible transgene expression in clinically relevant patient-derived xenograft (PDX) models in vivo to fill this gap. Results With this technique at hand, we analyzed the role of the transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive preclinical in vivo trials, we found that re-expression of wild type KLF4 reduced the leukemia load in PDX models of B-ALL, with the strongest effects being observed after conventional chemotherapy in minimal residual disease (MRD). A nonfunctional KLF4 mutant had no effect on this model. The re-expression of KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. It is of major translational relevance that azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced azacitidine-induced cell death, suggesting that azacitidine can regulate KLF4 re-expression. These results support the application of azacitidine in patients with B-ALL as a therapeutic option to regulate KLF4. Conclusion Genetic engineering of PDX models allows the examination of the function of dysregulated genes like KLF4 in a highly clinically relevant translational context, and it also enables the selection of therapeutic targets in individual tumors and links their functions to clinically available drugs, which will facilitate personalized treatment in the future.

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A KLF4-DYRK2–mediated pathway regulating self-renewal in CML stem cells

Abstract: Park et al describe a novel KLF4-mediated pathway that promotes chromic myeloid leukemia (CML) stem cell (LSC) survival. Deletion of KLF4 in a mouse model of CML decreases LSC survival through repression of Dyrk2, resulting in c-Myc depletion and increased p53 activity.

Cited by 36 publications

References 67 publications

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells

Inducible transgene expression in PDX models in vivo identifies KLF4 as a therapeutic target for B-ALL

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