Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome

Abstract

Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression.

IPSS‐R in 555 Taiwanese patients with primary MDS: Integration of monosomal karyotype can better risk‐stratify the patients

“…It has been shown that IPSS-R predicts survival and leukemic evolution in MDS patients significantly better than IPSS in Western countries [5][6][7][8]. Since the demographics and disease natures in MDS patients are different between Asian and Western countries [9][10][11][12], it is unclear whether this new risk model is similarly useful for risk stratification of MDS in Asia. The primary aim of this study is to externally validate the prognostic power of this new risk model in a large cohort of patients with primary MDS in Taiwan.…”

A 4-lncRNA scoring system for prognostication of adult myelodysplastic syndromes

“…Cytogenetic analyses were performed as described previously, 39 and interpreted according to the International System for Human Cytogenetic Nomenclature. 40 Mutation analyses of 17 genes relevant to myeloid malignancies, such as genes related to epigenetic regulation (including ASXL1, 41 52 were performed by Sanger sequencing as previously described. Abnormal sequencing results were confirmed by at least 2 repeated analyses.…”

SETBP1 mutations drive leukemic transformation of ASXL1-mutated MDS

“…22,26 All patients signed informed consents for sample collection in accordance with the Declaration of Helsinki. The clinical portion of this study was approved by the Institutional Review Board of the NTUH (approval 201207075RIB).…”

“…However, given that ASXL1 mutations have been linked to high-risk MDS and leukemic transformation of MDS, further studies to identify the mechanistic basis for transformation of ASXL1-mutated low-risk MDS to high-risk MDS/AML are needed. [21][22][23] In multiple clinical studies with large cohorts of MDS samples, ASXL1 mutations have been reported to be statistically associated with mutations in RUNX1, EZH2, SRSF2, STAG2, NRAS, and SET binding protein 1 (SETBP1). 4,22,24 In particular, mutations in NRAS and SETBP1 appear to occur after initial establishment of MDS, suggesting that these mutations contribute to disease progression or evolution.…”

“…[21][22][23] In multiple clinical studies with large cohorts of MDS samples, ASXL1 mutations have been reported to be statistically associated with mutations in RUNX1, EZH2, SRSF2, STAG2, NRAS, and SET binding protein 1 (SETBP1). 4,22,24 In particular, mutations in NRAS and SETBP1 appear to occur after initial establishment of MDS, suggesting that these mutations contribute to disease progression or evolution. 4,[25][26][27] Consistent with this, we previously revealed that ASXL1-MT or ASXL1-knockdown collaborated with NRAS mutations to induce AML.…”