Malignant Transformation Involving CXXC4 Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia

Cell Reports Medicine
Patricia A OlofsenI P Touw

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.

Citations

May 11, 2021·Frontiers in Immunology·Zuzanna RydzynskaJoanna Madzio
Jun 24, 2021·Acta Paediatrica·Bengt FadeelMagnus Nordenskjöld

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Datasets Mentioned

BETA
E-MTAB-9373
E-MTAB-9377
E-MTAB-9381
E-MTAB-9376
E-MTAB-9375
E-MTAB-9374

Methods Mentioned

BETA
MDS
fluorescence-activated cell sorting
flow cytometry
X-ray
transfection
PCR
FACS
amplicon sequencing
exome sequencing

Key Resources (RRID) Mentioned

Addgene_1764
Addgene_12371
Addgene_12260
Addgene_12259
Addgene_42230

Software Mentioned

GraphPad Prism
GSEA
R
CASAVA
count
Cufflinks
HTSeq
MultiQC
GraphPad
GraphPadPrism

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