Mol. Cells 2020; 43(2): 139-144
Published online February 3, 2020
https://doi.org/10.14348/molcells.2020.0010
© The Korean Society for Molecular and Cellular Biology
Correspondence to : *Correspondence: i.touw@erasmusmc.nl
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
Somatic RUNX1 mutations are found in approximately 10% of patients with de novo acute myeloid leukemia (AML), but are more common in secondary forms of myelodysplastic syndrome (MDS) or AML. Particularly, this applies to MDS/AML developing from certain types of leukemia-prone inherited bone marrow failure syndromes. How these RUNX1 mutations contribute to the pathobiology of secondary MDS/AML is still unknown. This mini-review focusses on the role of RUNX1 mutations as the most common secondary leukemogenic hit in MDS/AML evolving from severe congenital neutropenia (SCN).
Keywords leukemic progression, RUNX1, severe congenital neutropenia
The occurrence and frequency of
SCN is an iBMF characterized by severely reduced neutrophil counts, leading to life-threatening bacterial infections (Skokowa et al., 2017). Autosomal dominant mutations in
Like for numerous other disease conditions, the introduction of massive parallel (“next generation”) sequencing has greatly advanced our insights into the genomic defects associated with the leukemic progression of SCN. A retrospective analysis in an ELANE-SCN patient, who continuously received CSF3 therapy for 15 years and during which period serial BM sampling was done, showed that after the occurrence of multiple CSF3R mutant clones 2 years after the start of CSF3 treatment, no additional mutations were detected until MDS/AML became clinically overt (Beekman et al., 2012). At that fully transformed stage, a limited number of clonal mutations in regulatory genes, including
The impact of Runx1 and mutants on hematopoietic cell development has been investigated in a variety of mouse models and has been the subject of several recent reviews (Bellissimo and Speck, 2017; Chin et al., 2015; Harada and Harada, 2009; Sood et al., 2017). Notwithstanding some contradictory results, possibly related to discrepancies in the immune-phenotyping based classification of stem cell subpopulations, it is generally accepted that wild type Runx1 has no major impact on the production and function of long-term hematopoietic stem cells in mice, both under homeostatic conditions and under conditions of proliferative stress (Cai et al., 2011). More relevant in the context of
To study the role of RUNX1-D171N in a context relevant to SCN-MDS/AML, we used a mouse model expressing a truncated Csf3r (Csf3r-d715) identical to the mutant CSF3R form in SCN patients (Hermans et al., 1998; 1999). To avoid the tropism of MLV-based vectors for oncogenic enhancers, we generated a lentiviral expression vector to express RUNX1 mutant D171N (Goyama et al., 2013) in conjunction with enhanced green fluorescent protein (eGFP) in Csf3r-d715 BM cells, which were subsequently serially transplanted in wild type recipients. Recipients were treated either 3× a week with CSF3 or with PBS (solvent control). Transcriptome analysis and whole exome sequencing on FACS purified eGFP+Lin–c-Kit+ (LK) populations were done to identify molecular pathways associated with leukemic progression. Sequential CD34+ cell samples from a SCN/AML patient with identical
CSF3 treatment of primary recipients transplanted with
The use of patient-derived iPSC lines has created new possibilities to model diseases, including myeloid malignancies (Papapetrou, 2019). In the context of
The role of
This work was financially supported by grants from the Dutch Cancer Society “KWF-kankerbestrijding”.
The authors have no potential conflicts of interest to disclose.
Mol. Cells 2020; 43(2): 139-144
Published online February 29, 2020 https://doi.org/10.14348/molcells.2020.0010
Copyright © The Korean Society for Molecular and Cellular Biology.
Patricia A. Olofsen and Ivo P. Touw*
Department of Hematology, Erasmus MC, Rotterdam 3015 CN, The Netherlands
Correspondence to:*Correspondence: i.touw@erasmusmc.nl
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
Somatic RUNX1 mutations are found in approximately 10% of patients with de novo acute myeloid leukemia (AML), but are more common in secondary forms of myelodysplastic syndrome (MDS) or AML. Particularly, this applies to MDS/AML developing from certain types of leukemia-prone inherited bone marrow failure syndromes. How these RUNX1 mutations contribute to the pathobiology of secondary MDS/AML is still unknown. This mini-review focusses on the role of RUNX1 mutations as the most common secondary leukemogenic hit in MDS/AML evolving from severe congenital neutropenia (SCN).
Keywords: leukemic progression, RUNX1, severe congenital neutropenia
The occurrence and frequency of
SCN is an iBMF characterized by severely reduced neutrophil counts, leading to life-threatening bacterial infections (Skokowa et al., 2017). Autosomal dominant mutations in
Like for numerous other disease conditions, the introduction of massive parallel (“next generation”) sequencing has greatly advanced our insights into the genomic defects associated with the leukemic progression of SCN. A retrospective analysis in an ELANE-SCN patient, who continuously received CSF3 therapy for 15 years and during which period serial BM sampling was done, showed that after the occurrence of multiple CSF3R mutant clones 2 years after the start of CSF3 treatment, no additional mutations were detected until MDS/AML became clinically overt (Beekman et al., 2012). At that fully transformed stage, a limited number of clonal mutations in regulatory genes, including
The impact of Runx1 and mutants on hematopoietic cell development has been investigated in a variety of mouse models and has been the subject of several recent reviews (Bellissimo and Speck, 2017; Chin et al., 2015; Harada and Harada, 2009; Sood et al., 2017). Notwithstanding some contradictory results, possibly related to discrepancies in the immune-phenotyping based classification of stem cell subpopulations, it is generally accepted that wild type Runx1 has no major impact on the production and function of long-term hematopoietic stem cells in mice, both under homeostatic conditions and under conditions of proliferative stress (Cai et al., 2011). More relevant in the context of
To study the role of RUNX1-D171N in a context relevant to SCN-MDS/AML, we used a mouse model expressing a truncated Csf3r (Csf3r-d715) identical to the mutant CSF3R form in SCN patients (Hermans et al., 1998; 1999). To avoid the tropism of MLV-based vectors for oncogenic enhancers, we generated a lentiviral expression vector to express RUNX1 mutant D171N (Goyama et al., 2013) in conjunction with enhanced green fluorescent protein (eGFP) in Csf3r-d715 BM cells, which were subsequently serially transplanted in wild type recipients. Recipients were treated either 3× a week with CSF3 or with PBS (solvent control). Transcriptome analysis and whole exome sequencing on FACS purified eGFP+Lin–c-Kit+ (LK) populations were done to identify molecular pathways associated with leukemic progression. Sequential CD34+ cell samples from a SCN/AML patient with identical
CSF3 treatment of primary recipients transplanted with
The use of patient-derived iPSC lines has created new possibilities to model diseases, including myeloid malignancies (Papapetrou, 2019). In the context of
The role of
This work was financially supported by grants from the Dutch Cancer Society “KWF-kankerbestrijding”.
The authors have no potential conflicts of interest to disclose.
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