Abstract
Recent progress in deep sequencing technologies has revealed many novel mutations in a variety of genes in patients with myelodysplastic syndromes (MDS). Most of these mutations are thought to be loss-of-function mutations, with some exceptions, such as the gain-of-function IDH1/2 and SRSF2 mutations. Among the mutations, ASXL1 mutations attract much attention; the ASXL1 mutations are identified in a variety of hematologic malignancies and always predicts poor prognosis. It was found that the C-terminal truncating mutants of the ASXL1 or ASXL1 deletion induced MDS-like diseases in mouse. In addition, it has recently been reported that ASXL1 mutations are frequently found in clonal hematopoiesis in healthy elderly people, who frequently progress to hematologic malignancies. However, the underlying molecular mechanisms by which ASXL1 mutations induce hematologic malignancies are not fully understood. Moreover, whether ASXL1 mutations are loss-of-function mutations or dominant-negative or gain-of-function mutations remains a matter of controversy. We here present solid evidence indicating that the C-terminal truncating ASXL1 protein is indeed expressed in cells harboring homozygous mutations of ASXL1, indicating the ASXL1 mutations are dominant-negative or gain-of-function mutations; for the first time, we detected the truncated ASXL1 proteins in two cell lines lacking the intact ASXL1 gene by mass spectrometry and Western blot analyses. Thus, together with our previous results, the present results indicate that the truncating ASXL1 mutant is indeed expressed in MDS cells and may play a role in MDS pathogenesis not previously considered.
| Original language | English |
|---|---|
| Pages (from-to) | 172-176.e1 |
| Journal | Experimental Hematology |
| Volume | 44 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 1 2016 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Hematology
- Genetics
- Cell Biology
- Cancer Research
Cite this
Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels. / Inoue, Daichi; Matsumoto, Masaki; Nagase, Reina; Saika, Makoto; Fujino, Takeshi; Nakayama, Keiichi; Kitamura, Toshio.
In: Experimental Hematology, Vol. 44, No. 3, 01.03.2016, p. 172-176.e1.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels
AU - Inoue, Daichi
AU - Matsumoto, Masaki
AU - Nagase, Reina
AU - Saika, Makoto
AU - Fujino, Takeshi
AU - Nakayama, Keiichi
AU - Kitamura, Toshio
PY - 2016/3/1
Y1 - 2016/3/1
N2 - Recent progress in deep sequencing technologies has revealed many novel mutations in a variety of genes in patients with myelodysplastic syndromes (MDS). Most of these mutations are thought to be loss-of-function mutations, with some exceptions, such as the gain-of-function IDH1/2 and SRSF2 mutations. Among the mutations, ASXL1 mutations attract much attention; the ASXL1 mutations are identified in a variety of hematologic malignancies and always predicts poor prognosis. It was found that the C-terminal truncating mutants of the ASXL1 or ASXL1 deletion induced MDS-like diseases in mouse. In addition, it has recently been reported that ASXL1 mutations are frequently found in clonal hematopoiesis in healthy elderly people, who frequently progress to hematologic malignancies. However, the underlying molecular mechanisms by which ASXL1 mutations induce hematologic malignancies are not fully understood. Moreover, whether ASXL1 mutations are loss-of-function mutations or dominant-negative or gain-of-function mutations remains a matter of controversy. We here present solid evidence indicating that the C-terminal truncating ASXL1 protein is indeed expressed in cells harboring homozygous mutations of ASXL1, indicating the ASXL1 mutations are dominant-negative or gain-of-function mutations; for the first time, we detected the truncated ASXL1 proteins in two cell lines lacking the intact ASXL1 gene by mass spectrometry and Western blot analyses. Thus, together with our previous results, the present results indicate that the truncating ASXL1 mutant is indeed expressed in MDS cells and may play a role in MDS pathogenesis not previously considered.
AB - Recent progress in deep sequencing technologies has revealed many novel mutations in a variety of genes in patients with myelodysplastic syndromes (MDS). Most of these mutations are thought to be loss-of-function mutations, with some exceptions, such as the gain-of-function IDH1/2 and SRSF2 mutations. Among the mutations, ASXL1 mutations attract much attention; the ASXL1 mutations are identified in a variety of hematologic malignancies and always predicts poor prognosis. It was found that the C-terminal truncating mutants of the ASXL1 or ASXL1 deletion induced MDS-like diseases in mouse. In addition, it has recently been reported that ASXL1 mutations are frequently found in clonal hematopoiesis in healthy elderly people, who frequently progress to hematologic malignancies. However, the underlying molecular mechanisms by which ASXL1 mutations induce hematologic malignancies are not fully understood. Moreover, whether ASXL1 mutations are loss-of-function mutations or dominant-negative or gain-of-function mutations remains a matter of controversy. We here present solid evidence indicating that the C-terminal truncating ASXL1 protein is indeed expressed in cells harboring homozygous mutations of ASXL1, indicating the ASXL1 mutations are dominant-negative or gain-of-function mutations; for the first time, we detected the truncated ASXL1 proteins in two cell lines lacking the intact ASXL1 gene by mass spectrometry and Western blot analyses. Thus, together with our previous results, the present results indicate that the truncating ASXL1 mutant is indeed expressed in MDS cells and may play a role in MDS pathogenesis not previously considered.
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UR - http://www.scopus.com/inward/citedby.url?scp=84960098133&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2015.11.011
DO - 10.1016/j.exphem.2015.11.011
M3 - Article
C2 - 26700326
AN - SCOPUS:84960098133
VL - 44
SP - 172-176.e1
JO - Experimental Hematology
JF - Experimental Hematology
SN - 0301-472X
IS - 3
ER -