1.Progress of studies on genetics of childhood acute leukemia.
Journal of Experimental Hematology 2013;21(3):791-795
This study on determination of leukemia-specific chromosomal abnormalities and their relationship with prognosis of childhood acute leukemia (AL) had an important significance for childhood acute leukemia. In recent years, the efficacy of treatment of childhood AL has been greatly improved, but relapse is still a main factor affecting prognosis. Treatment based on the risk stratification by cytogenetic abnormalities can improve the prognosis and survival rate. In the past 3 decades, the genetic techniques have developed rapidly and many new genetic abnormalities have been found. This review highlights the main chromosomal and genomic abnormalities of 3 common childhood AL, including B-cell precursor acute lymphoblastic leukemia (BCP-ALL), T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
Acute Disease
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Child
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Humans
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Leukemia
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genetics
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Leukemia, Myeloid, Acute
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genetics
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
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genetics
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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genetics
2.Clinical Study on the Relationship between Gene Mutation Profile and Prognosis in Pediatric Acute Lymphocyte Leukemia.
Yan CHEN ; Shan-Shan QI ; Li-Li DING ; Yu DU ; Na SONG ; Zhuo WANG ; Li YANG ; Ming SUN ; Hao XIONG
Journal of Experimental Hematology 2023;31(1):17-24
OBJECTIVE:
To analyze the gene mutation profile in children with acute lymphocyte leukemia (ALL) and to explore its prognostic significance.
METHODS:
Clinical data of 249 primary pediatric ALL patients diagnosed and treated in the Department of Hematological Oncology of Wuhan Children's Hospital from January 2018 to December 2021 were analyzed retrospectively. Next-generation sequencing (NGS) was used to obtain gene mutation data and analyze the correlation between it and the prognosis of children with ALL.
RESULTS:
227 (91.2%) were B-ALL, 22 (8.8%) were T-ALL among the 249 cases, and 178 (71.5%) were found to have gene mutations, of which 85 (34.1%) had ≥3 gene mutations. NRAS(23.7%), KRAS (22.9%),FLT3(11.2%), PTPN11(8.8%), CREBBP (7.2%), NOTCH1(6.4%) were the most frequently mutated genes, the mutations of KRAS, FLT3, PTPN11, CREBBP were mainly found in B-ALL, the mutations of NOTCH1 and FBXW7 were mainly found in T-ALL. The gene mutation incidence of T-ALL was significantly higher than that of B-ALL (χ2= 5.573,P<0.05) and were more likely to have co-mutations (P<0.05). The predicted 4-year EFS rate (47.9% vs 88.5%, P<0.001) and OS rate (53.8% vs 94.1%, P<0.001) in children with tp53 mutations were significantly lower than those of patients without tp53 mutations. Patients with NOTCH1 mutations had higher initial white blood cell count (128.64×109/L vs 8.23×109/L,P<0.001), and children with NOTCH1 mutations had a lower 4-year EFS rate than those of without mutations (71.5% vs 87.2%, P=0.037).
CONCLUSION
Genetic mutations are prevalent in childhood ALL and mutations in tp53 and NOTCH1 are strong predictors of adverse outcomes in childhood ALL, with NGS contributing to the discovery of genetic mutations and timely adjustment of treatment regimens.
Child
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Humans
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
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Cell Cycle Proteins/genetics*
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Proto-Oncogene Proteins p21(ras)/genetics*
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Retrospective Studies
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Ubiquitin-Protein Ligases/genetics*
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Prognosis
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Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
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Mutation
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Lymphocytes
4.Research advance on the pathogenesis of T-ALL induced by notch 1 activating mutations.
Shuang-Nian XU ; Jie-Ping CHEN
Journal of Experimental Hematology 2010;18(1):242-245
T-cell acute lymphoblastic leukemia (T-ALL) is the hematological malignancy of bone marrow characterized by the rapid proliferation and subsequent accumulation of immature T lymphocyte and mainly occurs in children and adolescents. In 1991, a kind of activating mutation of Notch 1 was found in a subset of T-ALL with chromosomal translocation t(7;9) for the first time. During the past 20 years since then, understanding of the relationship between Notch 1 activating mutation and T-ALL has been deepened and widened. This review briefly discusses the four main subtypes of Notch 1 activating mutations, also focuses on how these mutations change the normal signaling pathways and genes expression during their participation in the pathogenesis of T-ALL, and how these insights will promote the development of newly targeting therapies for patients with this aggressive form of leukemia.
Humans
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Mutation
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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etiology
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genetics
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Receptor, Notch1
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genetics
5.Immunophenotypic and Clinical Characteristics of SET-CAN Fusion Gene Positive Acute Leukemia Patients.
Song-Ya LIU ; Li ZHU ; Chun-Yan WANG ; Cheng HE ; Shu-Juan YI ; Li MENG ; Min XIAO ; Xia MAO
Journal of Experimental Hematology 2023;31(6):1639-1646
OBJECTIVE:
To analyze the flow immunophenotype and clinical characteristics of leukemia patients with positive SET-CAN fusion gene.
METHODS:
A total of 7 newly diagnosed acute leukemia patients with SET-CAN fusion gene admitted to Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology from February 2016 to February 2020 were collected. Multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the expression of SET-CAN fusion gene. The immunophenotype was detected by four-color flow cytometry. The case information of 17 literatures published at home and abroad was extracted for statistical analysis.
RESULTS:
Among the 7 patients, 2 cases were diagnosed as mixed phenotype acute leukemia (MPAL), 2 cases as acute myeloid leukemia (AML), and 3 cases as T-acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). Leukemia cells in bone marrow specimens of all cases expressed or partially expressed CD34, CD33 and CD7. CD5 and cytoplasmic CD3 were expressed in 5 patients except 2 patients diagnosed with AML. Bone marrow and lymph node specimens were both detected in 2 patients, and the immunophenotypes of the two specimens were not completely consistent, with differences in lineage or maturity related markers. Two patients with MPAL showed differentiated response to treatment. One AML patient gave up treatment, and another AML patient with FLT3-ITD gene mutation had a poor prognosis. All three T-ALL/LBL patients maintained a long duration of remission after induced remission, and one case underwent allogeneic hematopoietic stem cell transplantation.
CONCLUSIONS
There are common characteristics of immunophenotype in patients with positive SET-CAN fusion gene. Differential expression of immunophenotype in samples from different parts is observed in some cases. The prognosis of these diseases varies.
Humans
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Leukemia, Myeloid, Acute/pathology*
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Bone Marrow/pathology*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*
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Antigens, CD34
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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Immunophenotyping
6.Gene Mutation in Acute Lymphoblastic Leukemia by DNA Sequencing.
Ru-Yue ZHENG ; Shu-Juan WANG ; Chong WANG ; Tao LI ; Lin-Xiao LIAO ; Meng-Lin LI ; Sheng-Mei CHEN ; Rong GUO ; Wei-Qiong WANG ; Yu ZHANG ; Yi FAN ; Ding-Ming WAN ; Yan-Fang LIU
Journal of Experimental Hematology 2020;28(6):1791-1795
OBJECTIVE:
To analyze the characteristics of gene mutation in adult ALL and its clinical significance.
METHODS:
Clinical data of 134 primary adult ALL patients and DNA sequencing results of 16 kinds of gene mutation were collected. The characteristic of gene mutation and clinical significances were statistically analyzed.
RESULTS:
In 31 cases of 134 ALL cases (23.13%) the gene mutations were detected as follows: 19 cases of 114 B-ALL cases (16.67%), 11 cases of 19 T-ALL cases (57.89%) and 1 case of T/B-ALL. The incidence of T-ALL gene mutation was significantly higher than that of B-ALL (χ
CONCLUSION
There may be multiple gene mutations in adult ALL patients. IL7R and NOTCH1 are the most common gene mutations and NOTCH1 mutation may indicate poor prognosis. Detection of gene mutations is helpful to understand the pathogenesis of ALL and evaluate the prognosis of adult ALL patients.
Adult
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Humans
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Mutation
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Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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Prognosis
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Receptor, Notch1/genetics*
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Sequence Analysis, DNA
7.β-arrestin1 Promotes the Concentration of Mitochondrial Reactive Oxygen in T-ALL Cells via MiR-652-5p.
Hao-Biao WANG ; Shan LIU ; Wei GUO ; Hai-Yan LIU ; Jie YU ; Lin ZOU
Journal of Experimental Hematology 2021;29(5):1456-1461
OBJECTIVE:
To investigate the effect of β-arrestin1 on the concentration of reactive oxygen species (ROS) in the mitochondria of acute T-lymphocytic leukemia (T-ALL) cells and its possible mechanisms.
METHODS:
The stable T-ALL cell line with knocked down β-arrestin1 (Jurkat Siβ1) was constructed. Flow cytometry and probe assays were used to detect ROS content in cell and mitochondrial, respectively. The relationship between β-arrestin1 and microRNA was detected, analyzed and Q-PCR confirmed by microRNA microarray. The target genes of microRNA were predicated by miRbase software, identified by Western blot, and validated by Dual luciferase reporter gene.
RESULTS:
Jurkat Siβ1 stable cell line was successfully constructed and it was found that ROS content was slightly reduced in Jurkat Siβ1 at the whole cell level, and the ROS content was also significantly reduced in mitochondria. MicroRNA microarray analysis revealed that multiple T-ALL related microRNAs showed differentially expressed, in which the expression of miR-652-5p was significantly increased in Jurkat Siβ1 (P<0.05 fold>2.0), and Q-PCR showed that miR-652-5p was nearly 5-fold up-regulated in Jurkat Siβ1. miRbase predicted that the P62 gene was the target gene of miR-652-5p which could regulates mitochondrial function. P62 protein showed highly expressed in stably knocked down miR-652-5p in Jurkat cells. Dual luciferase reporter gene assay confirms that P62 was the target gene of miR-652-5p.
CONCLUSION
β-arrestin1 can decreases the expression of miR-652-5p and deregulates the translational inhibition of P62 mRNA, thus to increase ROS content in mitochondria of T-ALL cells.
Humans
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MicroRNAs/genetics*
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Mitochondria
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Oxygen
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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RNA, Messenger
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beta-Arrestin 1
8.The Effect of KRAS on Proliferation and Apoptosis of T-ALL Cell Lines.
Zi-Yang LIU ; Yi SHU ; Guo FU ; Hong-Yu SU ; Dan ZHU ; La-Mei ZENG ; De-Yu MA ; Lin ZOU
Journal of Experimental Hematology 2022;30(4):1040-1048
OBJECTIVE:
To investigate the function of RAS protein on the progression of the T-ALL cell lines in vitro.
METHODS:
The DNA of the T-ALL cells was purified then amplified the coding regions of three RAS genes (KRAS, NRAS, HRAS) by PCR reaction. After T-A cloning, the coding regions of KRAS, NRAS and HRAS were sequenced by Sanger Sequencing. The siRNA oligonucleotides were cloned into the pSEH-361 vector, which were then packaged into retroviral together with pAMPHO and pVSVG in the HEK-293T cells. The T-ALL cells were infected with the retrovirus. The gene expressions were detected by qRT-PCR and Western blot. The T-ALL cells were stained with Annexin V-PE/7-AAD and the apoptotic cells were detected by flow cytometry. The T-ALL cells were stained with Hoechst 33258, and the cell cycle distribution was determined by flow cytometry. The expression of cleaved-Caspase 3 was stained with antibody and observed with fluorescence microscope.
RESULTS:
For RAS genes, beside the Loucy and the P12-ICH cells harbored KRAS c.6187G>A (p.KRASG12D) homozygous mutant, no missense mutation of RAS was found in other T-ALL cells genome. The pan RAS inhibitor compound 3144 showed toxicity to all tested T-ALL cells, except PEER (IC50=47.916 μmol/L). Similarly, Tipifarnib induced apoptosis of multiple T-ALL cell lines except for the PEER cells (IC50=94.2265 μmol/L). After KRAS knock-down, the T-ALL cells showed significant apoptosis and an arrested cell cycle.
CONCLUSION
The KRAS protein is vital for the progression of the T-ALL cells in vitro, it is a potential therapeutic target for T-ALL patients.
Apoptosis
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Cell Line
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Cell Proliferation
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Humans
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Mutation
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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Proto-Oncogene Proteins p21(ras)/genetics*
9.Clinicopathologic features and prognosis of T lymphoblastic lymphoma associated with Langerhans cell histiocytosis.
Xinxia LI ; Ye WANG ; Rong CHEN ; Dilinazi ABULAITI ; Zhiping MA ; Na MIAO ; Gulinaer ABULAJIANG ; Wei ZHANG
Chinese Journal of Pathology 2014;43(8):522-527
OBJECTIVETo study the clinicopathologic features, immunophenotype and molecular genetic changes of T lymphoblastic lymphoma (T-LBL) associated with Langerhans cell histiocytosis (LCH).
METHODSThree cases of T-LBL associated with LCH were included. The morphologic characteristics were reviewed along with immunohistochemical profiling using EnVision method and TCR gene rearrangement by PCR. A review of composite lymphoma previously reported in the literature was performed.
RESULTSAll three patients were male with the mean age of 61.7 years. One was Hans and the other 2 were Uyguers. All presented with superficial lymph node enlargement. Biopsy of lymph node showed two abnormal cell populations: distended sinus by large, pale histiocytes with nuclear grooves, and the interfollicular region containing immature-appearing cells with irregular nuclei slightly larger than that of small lymphocyte, dispersed chromatin, inconspicuous nucleoli, scant cytoplasm, and scattered mitotic figures. These cells presented in aggregates and small sheets interspersed with normal-appearing lymphocyte. The histiocytes were positive for CD1a, S-100 protein and CD68. The lymphoma cells were positive for CD3, CD7, TdT and CD34. TCR-γ gene rearrangement was detected in one case by PCR technology. One case involved bone marrow with double phenotype acute leukemia. Amongst the 8 including 5 reported cases, there were 4 males and 4 females. The mean age of the patients and the median age were 54 years. Lymphoadenopathy was the most common presentation. Bone marrow was involved in 4 cases. The time of follow-up was 2 to 27 months. The median survival was 5.5 months and the one-year survival rate was 33.3%.
CONCLUSIONSDiagnosis of T-LBL and LCH should be based on typical morphology, immunophenotype and molecular genetic findings, with differential diagnoses including Langerhans cell hyperplasia originated from dermatopathic lymphadenopathy. When involving lymph node, extensive sampling supplemented by immunohistochemical staining is important to reach a correct diagnosis. Although coexistent T-LBL and LCH is clonally related, the understanding of its pathogenesis requires further investigation.
Bone Marrow ; pathology ; Female ; Gene Rearrangement ; Histiocytosis, Langerhans-Cell ; genetics ; pathology ; Humans ; Immunophenotyping ; Leukemia ; genetics ; Lymph Nodes ; pathology ; Male ; Middle Aged ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; pathology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; pathology ; Prognosis
10.Biological characteristics of T-lineage acute lymphoblastic leukemia in 23 children.
Hao XIONG ; Yao-Dong ZHANG ; Qun HU ; Yan SUN ; Shuang-You LIU ; Liu-Qing ZHANG ; Ai-Guo LIU ; Guan-Ling WANG
Chinese Journal of Contemporary Pediatrics 2010;12(8):605-608
OBJECTIVETo investigate the biological characteristics of childhood T-lineage acute lymphoblastic leukemia (T-ALL) and their clinical significance.
METHODSImmunophenotyping was performed by three-color flow cytometry analysis using CD45 /SSC gating in 23 children with newly diagnosed T-ALL. Meanwhile cytogenetic analysis was performed.
RESULTSCD3(+) expression of T-lineage antigens was apparently higher than CD7(+) and CD5(+) expression. CD19(+) expression of B-lineage antigens was apparently higher than CD22(+), CD10(+) and CD20(+) expression. Myeloid antigen was expressed in 4 cases (17%). CD34(+) and HLA-DR(+) were observed in 4 cases (17%) and 5 cases (22%), respectively. cCD3(+) and cCD79(+) were expressed in 23 cases (100%) and 22 cases (96%), respectively. The chromosome detection in 8 cases with T-ALL showed hyperdiploid or Ph(+) chromosome (one case each). The fusion gene detection in 5 cases showed MLL rearrangements in two cases and positive SIL/TAL1 fusion gene in one case. CD3 expression was related with the complete remission rate.
CONCLUSIONSImmunophenotyping is an important tool for diagnosis of T-ALL. However, the immunophenotype of T-ALL is heterogeneous. So, immunophenotyping along with cytogenetic and molecular genetic analysis is needed in the treatment and prognosis evaluation of T-ALL.
Child ; Child, Preschool ; Chromosome Aberrations ; Female ; Humans ; Immunophenotyping ; Male ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; genetics ; immunology