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

doi:10.1016/j.xcrm.2020.100074

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 journal › Article › Academic › peer-review

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 language	English
Article number	100074
Journal	Cell Reports Medicine
Volume	1
Issue number	5
DOIs	https://doi.org/10.1016/j.xcrm.2020.100074
Publication status	Published - 25 Aug 2020
Externally published	Yes

Keywords

AML
CSF3R
CXXC4
growth factor therapy
leukemia predisposition
pro-inflammatory signaling
RUNX1
severe congenital neutropenia
TET2

Access to Document

10.1016/j.xcrm.2020.100074

Cite this

Olofsen, P. A., Fatrai, S., van Strien, P. M. H., Obenauer, J. C., de Looper, H. W. J., Hoogenboezem, R. M., Erpelinck-Verschueren, C. A. J., Vermeulen, M. P. W. M., Roovers, O., Haferlach, T., Jansen, J. H., Ghazvini, M., Bindels, E. M. J., Schneider, R. K., de Pater, E. M., & Touw, I. P. (2020). Malignant Transformation Involving CXXC4 Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia. Cell Reports Medicine, 1(5), Article 100074. https://doi.org/10.1016/j.xcrm.2020.100074

@article{5dfc5c52fe6d4c77aa3bbc0ad26bcc2f,

title = "Malignant Transformation Involving CXXC4 Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia",

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.",

keywords = "AML, CSF3R, CXXC4, growth factor therapy, leukemia predisposition, pro-inflammatory signaling, RUNX1, severe congenital neutropenia, TET2",

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

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = aug,

day = "25",

doi = "10.1016/j.xcrm.2020.100074",

language = "English",

volume = "1",

number = "5",

}

Olofsen, PA, Fatrai, S, van Strien, PMH, Obenauer, JC, de Looper, HWJ, Hoogenboezem, RM, Erpelinck-Verschueren, CAJ, Vermeulen, MPWM, Roovers, O, Haferlach, T, Jansen, JH, Ghazvini, M, Bindels, EMJ, Schneider, RK, de Pater, EM & Touw, IP 2020, 'Malignant Transformation Involving CXXC4 Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia', Cell Reports Medicine, vol. 1, no. 5, 100074. https://doi.org/10.1016/j.xcrm.2020.100074

TY - JOUR

T1 - Malignant Transformation Involving CXXC4 Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia

AU - Olofsen, Patricia A.

AU - Fatrai, Szabolcs

AU - van Strien, Paulina M.H.

AU - Obenauer, Julia C.

AU - de Looper, Hans W.J.

AU - Hoogenboezem, Remco M.

AU - Erpelinck-Verschueren, Claudia A.J.

AU - Vermeulen, Michael P.W.M.

AU - Roovers, Onno

AU - Haferlach, Torsten

AU - Jansen, Joop H.

AU - Ghazvini, Mehrnaz

AU - Bindels, Eric M.J.

AU - Schneider, Rebekka K.

AU - de Pater, Emma M.

AU - Touw, Ivo P.

PY - 2020/8/25

Y1 - 2020/8/25

N2 - 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.

AB - 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.

KW - AML

KW - CSF3R

KW - CXXC4

KW - growth factor therapy

KW - leukemia predisposition

KW - pro-inflammatory signaling

KW - RUNX1

KW - severe congenital neutropenia

KW - TET2

UR - http://www.scopus.com/inward/record.url?scp=85096601900&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2020.100074

DO - 10.1016/j.xcrm.2020.100074

M3 - Article

C2 - 33205068

AN - SCOPUS:85096601900

SN - 2666-3791

VL - 1

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 5

M1 - 100074

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this