Bone marrow–confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia DOI Creative Commons
Yang Mei, Kehan Ren, Yijie Liu

et al.

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(17)

Published: July 28, 2022

Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with increased risk of progression to acute leukemia (AML). The mechanisms transformation MDS AML poorly understood, especially in relation the aging microenvironment. We previously established an mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop pancytopenia oversecretion proinflammatory cytokines. Here, we found that most DKO underwent leukemic at 12-14 months age. showed myeloblast replacement fibrotic bone marrow and widespread infiltration. Strikingly, depletion IL-6 these largely rescued markedly extended survival. Single-cell RNA sequencing analyses revealed had monocytic blasts were reduced knockout. further levels surface soluble receptor (IL-6R) significantly high-risk patients. Similarly, IL-6R was also highly expressed older mice. Blocking signaling ameliorated clonogenicity CD34-positive cells from Our study establishes a indicates clinical significance targeting treating

Language: Английский

Acute Myeloid Leukemia: Aging and Epigenetics DOI Open Access

Polina Zjablovskaja,

Maria Carolina Florian

Cancers, Journal Year: 2019, Volume and Issue: 12(1), P. 103 - 103

Published: Dec. 31, 2019

Acute myeloid leukemia (AML) is an aggressive hematological disorder mainly affecting people of older age. AML initiation primarily attributed to mutations in crucial cellular regulators such as epigenetic factors, transcription and signaling genes. AML’s aggressiveness responsiveness treatment depends on the specific cell type where first arose. Aged hematopoietic cells are often genetically and/or epigenetically altered and, therefore, present with a completely different context for development compared young cells. In this review, we summarize key aspects development, focus, particular, contribution aging leukemogenesis current options elderly patients. Hematological disorders grow exponentially So far, conventional induction therapy, many patients experience very poor overall survival rate requiring substantial social medical costs during relatively few remaining months life. The global population’s age increasing rapidly without acceptable equal growth therapeutic management elderly; sharp contrast increase successful therapies younger Therefore, focus understanding biology system, appropriate research models, new approaches urged.

Language: Английский

Citations

57
Current Methods of Post-Translational Modification Analysis and Their Applications in Blood Cancers DOI Open Access
Katie Dunphy, Paul Dowling, Despina Bazou

et al.

Cancers, Journal Year: 2021, Volume and Issue: 13(8), P. 1930 - 1930

Published: April 16, 2021

Post-translational modifications (PTMs) add a layer of complexity to the proteome through addition biochemical moieties specific residues proteins, altering their structure, function and/or localization. Mass spectrometry (MS)-based techniques are at forefront PTM analysis due ability detect large numbers modified proteins with high level sensitivity and specificity. The low stoichiometry peptides means fractionation enrichment often performed prior MS improve detection yields. Immuno-based remain popular, improvements in quality commercially available modification-specific antibodies facilitating affinity. PTM-focused studies on blood cancers have provided information altered cellular processes, including cell signaling, apoptosis transcriptional regulation, that contribute malignant phenotype. Furthermore, mechanism action many cancer therapies, such as kinase inhibitors, involves inhibiting or modulating protein modifications. Continued optimization protocols for will undoubtedly lead novel insights into mechanisms transformation, proliferation, survival, identification biomarkers therapeutic targets. This review discusses used applications research.

Language: Английский

Citations

50
Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets DOI Creative Commons
Tiansu Wang, Allison R. Pine, Andriana G. Kotini

et al.

Cell stem cell, Journal Year: 2021, Volume and Issue: 28(6), P. 1074 - 1089.e7

Published: Feb. 10, 2021

Language: Английский

Citations

48
Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications DOI
Nathaniel Long, Upendarrao Golla, Arati Sharma

et al.

Stem Cell Reviews and Reports, Journal Year: 2022, Volume and Issue: 18(4), P. 1211 - 1226

Published: Jan. 20, 2022

Language: Английский

Citations

36
Bone marrow–confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia DOI Creative Commons
Yang Mei, Kehan Ren, Yijie Liu

et al.

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(17)

Published: July 28, 2022

Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with increased risk of progression to acute leukemia (AML). The mechanisms transformation MDS AML poorly understood, especially in relation the aging microenvironment. We previously established an mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop pancytopenia oversecretion proinflammatory cytokines. Here, we found that most DKO underwent leukemic at 12-14 months age. showed myeloblast replacement fibrotic bone marrow and widespread infiltration. Strikingly, depletion IL-6 these largely rescued markedly extended survival. Single-cell RNA sequencing analyses revealed had monocytic blasts were reduced knockout. further levels surface soluble receptor (IL-6R) significantly high-risk patients. Similarly, IL-6R was also highly expressed older mice. Blocking signaling ameliorated clonogenicity CD34-positive cells from Our study establishes a indicates clinical significance targeting treating

Language: Английский

Citations

36