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

Patricia A Olofsen, Szabolcs Fatrai, Paulina M H van Strien, Julia C Obenauer, Hans W J de Looper, Remco M Hoogenboezem, Claudia A J Erpelinck-Verschueren, Michael P W M Vermeulen, Onno Roovers, Torsten Haferlach, Joop H Jansen, Mehrnaz Ghazvini, Eric M J Bindels, Rebekka K Schneider, Emma M de Pater, Ivo P Touw*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)
32 Downloads (Pure)

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.

Original languageEnglish
Article number100074
Pages (from-to)100074
JournalCell Reports Medicine
Volume1
Issue number5
DOIs
Publication statusPublished - 25 Aug 2020

Bibliographical note

© 2020 The Author(s).

Research programs

  • EMC MGC-02-82-01
  • EMC OR-01

Fingerprint

Dive into the research topics of 'Malignant Transformation Involving CXXC4 Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia'. Together they form a unique fingerprint.

Cite this