Abstract
The genetics of transformation from myelodysplastic syndrome to secondary acute myeloid leukemia.
Author
person
Zhenyu Zhang
Shandong Cancer Hospital and Institute, Shandong First Medical Universityand Shandong Academy of Medical Sciences, Jinan, Shandong, China
info_outline
Zhenyu Zhang, Hong Zhang, Yani Lin, Miaoqing Zhao, Kun Ru
Full text
Authors
person
Zhenyu Zhang
Shandong Cancer Hospital and Institute, Shandong First Medical Universityand Shandong Academy of Medical Sciences, Jinan, Shandong, China
info_outline
Zhenyu Zhang, Hong Zhang, Yani Lin, Miaoqing Zhao, Kun Ru
Organizations
Shandong Cancer Hospital and Institute, Shandong First Medical Universityand Shandong Academy of Medical Sciences, Jinan, Shandong, China, Sino-US Diagnostics Lab, Tianjin, China, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, Shandong Cancer Hospital and Institute, Shandong First Medical Universityand Shandong Academy of Medical Sciences, Jinan, China
Abstract Disclosures
Research Funding
Other Foundation
Wu Jieping Medical Foundation (320.6750.2022-22-37), Shandong Cancer Hospital Talent Project (RCYJ202201), National Natural Science Foundation of China (82071035), Natural Science Foundation of Shandong Province (ZR2022LZL001)
Background:
Gene mutations play key role in the transformation from myelodysplastic syndrome (MDS) to secondary acute myeloid leukemia (s-AML). The aim of this study was to explore the clonal progression pattern from MDS to s-AML.
Methods:
A total of 663 patients diagnosed with MDS (n = 291), s-AML (n = 86), and primary AML (p-AML) (n = 286, M3 excluded) were enrolled in this study from May 2018 to December 2021, and the median age was 57 year-old (range 1~88). The diagnosis was established according to the WHO criteria. The MDS patients were divided into low-risk MDS ( n = 158) and high-risk MDS (n = 133) according to 2012 IPSS-R. Next generation sequencing was performed to detect the mutations of entire coding regions of 112 genes related with hematologic tumors in all patients.
Results:
It was found that mutations from 31 genes occurred in both MDS and AML, including DNA methylation (
DNMT3A
,
TET2
,
IDH1
,
IDH2
,
WT1
), chromatin modification (
SETBP1,
ASXL1
,
EZH2
,
PHF6
), RNA splicing (
U2AF1
,
SF3B1
,
SRSF2
,
ZRSR2
), transcription regulation (
TP53, CEBPA,
RUNX1
,
ETV6
,
GATA2
,
BCOR
,
BCORL1
), signal transduction pathways (
NRAS
,
KRAS
,
PTPN11, NOTCH1
,
FLT3
,
JAK2
,
KIT
), and others (
NPM1, FAT, STAG2, DDX41
). By enrichment analysis, those mutations were classified into two categories: type A mutations (
FLT3
,
IDH1
,
NPM1
,
NRAS
,
PTPN11
,
WT1
,
CEBPA
) and type B mutations (
IDH2
,
KRAS
,
U2AF1
,
ZRSR2
,
SRSF2
,
STAG2
,
DNMT3A
,
EZH2
,
RUNX1
,
ETV6
,
TP53
). The type A genes were significantly enriched in p-AML than in MDS, while some type B mutations, particularly RNA splicing, were significantly enriched in MDS than in p-AML. The VAFs of type A mutations were significantly lower than those of type B mutations. The longitudinal analysis of 10 patients with s-AML revealed two main models of clonal evolution, linear evolution and clone sweeping. Although the two models differed in the disease development, new sub-clones appeared in 9/10 patients. Interestingly, many of the new mutations were type A mutations (n = 7, 7/10), and 7 out of 10 patients carried type B mutations when they were at MDS state. The VAF data also showed that the preexisting mutations were generally higher than the newly emerging genetic alterations. Finally, an individual case was used to delineate the clone evolution. The patient was initially diagnosed with 5q syndrome and
U2AF1
mutation (type B) was identified. After treatment, the patient experienced remission, and developed a new
ETV6
mutation while the clonal size of
U2AF1
decreased. When the patient relapsed, the clone size of
ETV6
decreased while
U2AF1
mutated clone size were amplified, a typical “clone sweeping” pattern. When the patient eventually transformed to s-AML, three type A mutations (
NRAS
,
KRAS
and
PTPN11
) appeared simultaneously.
Conclusions:
This study revealed that the type A mutations are mainly responsible for the progression of MDS to AML, and the type B mutations are related to the clonal origin of MDS.
3 organizations
18 drugs
18 targets
Organization
Sino-US Diagnostics LabDrug
FLT3Drug
IDH1Drug
NPM1Drug
NRAS G13RDrug
PTPN11Drug
WT1Drug
CEBPADrug
IDH2Drug
KRASDrug
U2AF1Drug
ZRSR2Drug
SRSF2Drug
STAG2Drug
DNMT3ADrug
EZH2Drug
RUNx1T1Drug
ETV6:RUNX1Drug
TP53Target
CEBPATarget
NRASTarget
KRAS G12CTarget
U2AF1Target
PTPN11 (Shp2)Target
SF3B1Target
IDH1Target
ETV6Target
STAG2Target
TP53Target
DNMT3ATarget
WT1Target
SRSF2Target
RUNx1T1Target
FLT3Target
EZH2Target
ZRSR2Target
IDH2