Genomic landscape of CD34+ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers.
Myelodysplastic syndrome (MDS) includes a group of diseases characterized by dysplasia of bone marrow myeloid lineages with ineffective hematopoiesis and frequent evolution to acute myeloid leukemia (AML). Whole-genome sequencing was performed in CD34(+) hematopoietic stem/progenitor cells (HSPCs) from eight cases of refractory anemia with excess blasts (RAEB), the high-risk subtype of MDS. The nucleotide substitution patterns were found similar to those reported in AML, and mutations of 96 protein-coding genes were identified. Clonal architecture analysis revealed the presence of subclones in six of eight cases, whereas mutation detection of CD34(+) versus CD34(-) cells revealed heterogeneity of HSPC expansion status. With 39 marker genes belonging to eight functional categories, mutations were analyzed in 196 MDS cases including mostly RAEB (n = 89) and refractory cytopenia with multilineage dysplasia (RCMD) (n = 95). At least one gene mutation was detected in 91.0% of RAEB, contrary to that in RCMD (55.8%), suggesting a higher mutational burden in the former group. Gene abnormality patterns differed between MDS and AML, with mutations of activated signaling molecules and NPM1 being rare, whereas those of spliceosome more common, in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression free survival.
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Lan
L
Xu
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Zhao-Hui
ZH
Gu
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Yang
Y
Li
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Jin-Li
JL
Zhang
Department of Hematology, Shanghai No. 6 People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; and.
Chun-Kang
CK
Chang
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Chun-Ming
CM
Pan
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Jing-Yi
JY
Shi
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Yang
Y
Shen
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Bing
B
Chen
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Yue-Ying
YY
Wang
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Lu
L
Jiang
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Jing
J
Lu
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Xin
X
Xu
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Jue-Ling
JL
Tan
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;
Yu
Y
Chen
Shanghai-Ministry of Science and Technology Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China.
Sheng-Yue
SY
Wang
Department of Hematology, Shanghai No. 6 People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; and zchen@stn.sh.cn lixiao3326@163.com sjchen@stn.sh.cn.
Xiao
X
Li
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China;Shanghai-Ministry of Science and Technology Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China zchen@stn.sh.cn lixiao3326@163.com sjchen@stn.sh.cn.
Zhu
Z
Chen
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200025, China; zchen@stn.sh.cn lixiao3326@163.com sjchen@stn.sh.cn.
Sai-Juan
SJ
Chen
D018952:Antigens, CD34 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D060965:Clonal Evolution; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D017422:Sequence Analysis, DNA / Q000379:methods
D018952:Antigens, CD34; D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D000090243:Nucleophosmin
clonal evolution; gene mutation pattern; prognostic stratification