New agents in acute myeloid leukemia (AML)

Park, Silvia; Cho, Byung Sik; Kim, Hee-Je

doi:10.5045/br.2020.s003

Cited by 23 publications

(20 citation statements)

References 48 publications

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“…Such advances reflect the feasibility of molecular targeted approaches to treat AML, especially those that impinge on protein kinases with critical roles in the maintenance of malignant phenotype. Therefore, the exploration of kinase inhibitors with potential anti-neoplastic effect could significantly contribute to maintaining the positive trend that we have witnessed in recent years [57]. Accordingly, here we show that the clinical-grade CK2 inhibitor CIGB-300 impairs AML cells proliferation and viability, and we provide mechanistic insights supporting this antileukemic effect.…”

Section: Discussionsupporting

confidence: 68%

“…After no considerable changes in AML therapy, growing knowledge in the molecular pathophysiology of this hematological disease is being reflected in therapeutics with the recent approval by the FDA of a number of novel agents [57]. Such advances reflect the feasibility of molecular targeted approaches to treat AML, especially those that impinge on protein kinases with critical roles in the maintenance of malignant phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

et al. 2021

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Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), an advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based CK2 inhibitor CIGB-300 on AML cells proliferation and viability. CIGB-300 internalization and subcellular distribution were also studied, and the role of B23/nucleophosmin 1 (NPM1), a major target for the peptide in solid tumors, was addressed by knock-down in model cell lines. Finally, pull-down experiments and phosphoproteomic analysis were performed to study CIGB-interacting proteins and identify the array of CK2 substrates differentially modulated after treatment with the peptide. Importantly, CIGB-300 elicited a potent anti-proliferative and proapoptotic effect in AML cells, with more than 80% of peptide transduced cells within three minutes. Unlike solid tumor cells, NPM1 did not appear to be a major target for CIGB-300 in AML cells. However, in vivo pull-down experiments and phosphoproteomic analysis evidenced that CIGB-300 targeted the CK2α catalytic subunit, different ribosomal proteins, and inhibited the phosphorylation of a common CK2 substrates array among both AML backgrounds. Remarkably, our results not only provide cellular and molecular insights unveiling the complexity of the CIGB-300 anti-leukemic effect in AML cells but also reinforce the rationale behind the pharmacologic blockade of protein kinase CK2 for AML-targeted therapy.

show abstract

Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Such advances have remarked the feasibility of molecular targeted approaches to treat AML, especially those that impinge on protein kinases with critical roles in the maintenance of malignant phenotype. Therefore, the exploration of kinase inhibitors with potential anti-neoplastic effect could significantly contribute to maintain the positive trend that we have witnessed in the last years [57]. Accordingly, here we showed that the clinical-grade CK2 inhibitor CIGB-300 impairs AML cells proliferation and viability, and provided mechanistic insights supporting this anti-leukemic effect.…”

Section: Discussionsupporting

confidence: 65%

“…After no considerable changes in AML therapy, growing knowledge in the molecular pathophysiology of this hematological disease is being reflected in therapeutics with the recent approval for the FDA of a number of novel agents [57]. Such advances have remarked the feasibility of molecular targeted approaches to treat AML, especially those that impinge on protein kinases with critical roles in the maintenance of malignant phenotype.…”

Section: Discussionmentioning

confidence: 99%

Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

Rosales

Perez

Ramón

et al. 2021

Preprint

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Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based CK2 inhibitor CIGB-300 on AML cells proliferation and viability. CIGB-300 internalization and subcellular distribution were also studied, and the role of B23/nucleophosmin 1 (NPM1), a major target for the peptide in solid tumors, was addressed by knock-down in model cell lines. Finally, pull-down experiments and phosphoproteomic analysis were performed to study CIGB-interacting proteins and identify the array of CK2 substrates differentially modulated after treatment with the peptide. Importantly, CIGB-300 elicited a potent anti-proliferative and proapoptotic effect in AML cells, with more than 80% of peptide transduced cells within three minutes. Unlike solid tumor cells, NPM1 did not appear to be a major target for CIGB-300 in AML cells. However, in vivo pull-down experiments and phosphoproteomic analysis evidenced that CIGB-300 targeted the CK2α catalytic subunit, different ribosomal proteins, and inhibited the phosphorylation of a common CK2 substrates array among both AML backgrounds. Remarkably, our results not only provide cellular and molecular insights unveiling the complexity of the CIGB-300 anti-leukemic effect in AML cells, but also reinforce the rationale behind the pharmacologic blockade of protein kinase CK2 for AML targeted therapy.

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“…In addition, somatic mutations involving CEBPa, FLT3, NPM1, and c-Kit have been used to assess prognosis [5]. Based on these tumor-derived biological characteristics, target-specific and immunological methods have been developed to treat AML [6]. Unlike de novo AML, secondary AML (sAML), transformed from myelodysplastic syndromes (MDS), shows unique genetic features.…”

mentioning

confidence: 99%

Somatic mutations of activated signaling genes, transcription factors, or tumor suppressors are a precondition for leukemic transformation from myelodysplastic syndromes: a sequencing analysis of 64 paired samples

Chang

et al. 2021

Preprint

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The transformation biology of secondary AML from MDS is still not fully understood. Here, we performed a large cohort of paired sequences including target, whole-exome and single cell sequencing to search AML transformation- related mutations (TRM). The results showed that fifty-five out of the 64 (85.9%) patients presented presumptive TRM involving activated signaling, transcription factors, or tumor suppressors. Most of TRM (63.6%, 35 cases) emerged at the leukemia transformation point. All five of the remaining nine patients analyzed by paired whole exome sequencing showed TRM which are not included in the reference targets. Single-cell sequencing indicated that the activated cell signaling route was related to TRM which take place prior to phenotypic development. Of note, defined TRM was limited to a small set of genes (less than ten, in the order: NRAS/KRAS, CEBPA, TP53, FLT3, RUNX1, CBL, PTPN11 and WT1, accounted for 91.0% of the mutations). In conclusion, somatic mutations involving in activated signaling, transcription factors, or tumor suppressors appeared to be a precondition for AML transformation from myelodysplastic syndromes. The TRM may be considered as new therapy targets.

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New agents in acute myeloid leukemia (AML)

Cited by 23 publications

References 48 publications

Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

Somatic mutations of activated signaling genes, transcription factors, or tumor suppressors are a precondition for leukemic transformation from myelodysplastic syndromes: a sequencing analysis of 64 paired samples

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