Back to Search
Start Over
Malignant Transformation Involving CXXC4 Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia.
- Source :
-
Cell reports. Medicine [Cell Rep Med] 2020 Aug 25; Vol. 1 (5), pp. 100074. Date of Electronic Publication: 2020 Aug 25 (Print Publication: 2020). - Publication Year :
- 2020
-
Abstract
- Severe congenital neutropenia (SCN) patients treated with CSF3/G-CSF to alleviate neutropenia frequently develop acute myeloid leukemia (AML). A common pattern of leukemic transformation involves the appearance of hematopoietic clones with CSF3 receptor ( CSF3R ) mutations in the neutropenic phase, followed by mutations in RUNX1 before AML becomes overt. To investigate how the combination of CSF3 therapy and CSF3R and RUNX1 mutations contributes to AML development, we make use of mouse models, SCN-derived induced pluripotent stem cells (iPSCs), and SCN and SCN-AML patient samples. CSF3 provokes a hyper-proliferative state in CSF3R / RUNX1 mutant hematopoietic progenitors but does not cause overt AML. Intriguingly, an additional acquired driver mutation in Cxxc4 causes elevated CXXC4 and reduced TET2 protein levels in murine AML samples. Expression of multiple pro-inflammatory pathways is elevated in mouse AML and human SCN-AML, suggesting that inflammation driven by downregulation of TET2 activity is a critical step in the malignant transformation of SCN.<br />Competing Interests: The authors declare no competing interests.<br /> (© 2020 The Author(s).)
- Subjects :
- Animals
Cell Line
Cell Line, Tumor
Cell Transformation, Neoplastic pathology
Core Binding Factor Alpha 2 Subunit genetics
HEK293 Cells
Humans
Inflammation genetics
Inflammation pathology
K562 Cells
Mice
Neutropenia genetics
Neutropenia pathology
Signal Transduction genetics
Cell Transformation, Neoplastic genetics
Congenital Bone Marrow Failure Syndromes genetics
Congenital Bone Marrow Failure Syndromes pathology
DNA-Binding Proteins genetics
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute pathology
Mutation genetics
Neutropenia congenital
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2666-3791
- Volume :
- 1
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell reports. Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 33205068
- Full Text :
- https://doi.org/10.1016/j.xcrm.2020.100074