2.Abnormal activation of tyrosine kinases and its role in the pathogenesis of hematological malignancies - review.
Journal of Experimental Hematology 2007;15(3):657-661
Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiation. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) or overexpression of these enzymes plays an etiologic role in several clonal hematopoietic malignancies. Other than the causative effect of PTK product of the bcr/abl fusion gene on chronic myelogenous leukemia (CML), more evidence suggests that mutated tyrosine kinases are pivotal in the pathogenesis of most of other chronic myeloproliferative disorders, such as chronic myelomonocytic leukemia (CMML) and hypereosinophilic syndrome (HES). And the exciting results in several dependent groups in 2005 showed that a single nucleotide JAK2 somatic mutation (JAK2V617F mutation) was found to be involved in the pathogenesis of polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (CIMF). In the leukogenesis of acute myeloid leukemias (AML), the losing of the control of the proliferation of hematopoietic progenitor cells was principally the results of the aberrant PTK activity, such as FLT3 and C-kit overexpression. It works together with the loss of function mutation genes in promoting progenitor cell differentiation to confer AML's phenotypes. These upregulated PTK molecules represent attractive disease-specific targets, to which a new class of therapeutic agents are being developed. This review focuses on abnormal tyrosine kinases that have been involved in the pathogenesis of hematopoietic malignancies.
Chromosome Aberrations
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Chromosomes, Human, Pair 22
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genetics
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Chromosomes, Human, Pair 9
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genetics
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Hematologic Neoplasms
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enzymology
;
etiology
;
genetics
;
Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
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enzymology
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etiology
;
genetics
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Mutation
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Protein-Tyrosine Kinases
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genetics
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metabolism
3.Clinical development of chimeric antigen receptor-T cell therapy for hematological malignancies.
Chinese Medical Journal 2023;136(19):2285-2296
Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development. Chimeric antigen receptor (CAR)-T cell therapy is the most widely applied cellular therapy. Since the Food and Drug Administration approved two CD19-CAR-T products for clinical treatment of relapsed/refractory acute lymphoblastic leukemia and diffuse large B cell lymphoma in 2017, five more CAR-T cell products were subsequently approved for treating multiple myeloma or B cell malignancies. Moreover, clinical trials of CAR-T cell therapy for treating other hematological malignancies are ongoing. Both China and the United States have contributed significantly to the development of clinical trials. However, CAR-T cell therapy has many limitations such as a high relapse rate, adverse side effects, and restricted availability. Various methods are being implemented in clinical trials to address these issues, some of which have demonstrated promising breakthroughs. This review summarizes developments in CAR-T cell trials and advances in CAR-T cell therapy.
Humans
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Receptors, Chimeric Antigen
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Receptors, Antigen, T-Cell/genetics*
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Immunotherapy, Adoptive/adverse effects*
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Hematologic Neoplasms/therapy*
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Multiple Myeloma/etiology*
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Cell- and Tissue-Based Therapy
4.Four Cases of Hematologic Malignancy Following Radioactive Iodine Therapy for Thyroid Cancer.
Mijeong IM ; Jin Kyung LEE ; Young Joon HONG ; Seok Il HONG ; Hye Jin KANG ; Im Il NA ; Baek Yeol RYOO ; Gi Jeong CHEON ; Ha Na LEE ; Yoon Hwan CHANG
The Korean Journal of Laboratory Medicine 2008;28(6):425-429
Ionizing radiation including I131 might produce chromosomal translocation, causing hematologic malignancy. The incidence of leukemia following radioactive iodine treatment for thyroid cancer has been reported to be approximately 0.1 to 2.0% in Western countries, whereas fewer cases have been reported in Korea. We hereby report four cases of secondary hematologic malignancy, who received iodine therapy for thyroid cancer after thyroidectomy: two cases of acute lymphoblastic leukemia with t(9;22)(q34;q11.2), a case of MDS with 5q deletion, and a case of MDS with normal karyotype. Three cases of hematologic malignancy have developed after cumulative dosage of less than 800 mCi. The treatment intervals in two cases were less than 12 months, and the other two cases had I131 therapy only once. Assessment of causality using the Naranjo probability scale for adverse drug reactions showed that a 'possible' relationship existed between the use of I131 and secondary hematologic malignancy in all of the four cases in this report.
Adult
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Chromosomes, Human, Pair 22
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Chromosomes, Human, Pair 5
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Chromosomes, Human, Pair 9
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Female
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Gene Deletion
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Hematologic Neoplasms/*diagnosis/genetics
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Humans
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Iodine Radioisotopes/*adverse effects/therapeutic use
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Leukemia, Radiation-Induced/*diagnosis/etiology
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Middle Aged
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Myelodysplastic Syndromes/diagnosis/genetics
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Neoplasms, Second Primary/*diagnosis/genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/genetics
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Thyroid Neoplasms/*radiotherapy
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Thyroidectomy
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Translocation, Genetic
5.TNF-related apoptosis-inducing ligand signaling pathway and hematopoietic malignancies.
Journal of Experimental Hematology 2002;10(5):472-477
TNF-related apoptosis-inducing ligand (TRAIL) is a newly identified member of the tumor necrosis factor (TNF) family. TRAIL induces apoptosis by activating caspase cascades, stimulating a loss of mitochondrial membrane potential (Delta Psim) and cytochrome C release in the FADD/caspase-8 dependent pathway. However, TRAIL can also trigger transcriptional activations of the pro-oncogene of c-fos, JNK, and NF-kappaB by other signaling pathways downstream of FADD/caspase-8. MAPK/ERK activation has a dominant protecting effect over apoptotic signaling from the death receptors. The functional expression of TRAIL by leukemic cells may be involved in tumor cells evasion of immunosurveillance. Somatic mutations of TRAIL-R1 and TRAIL-R2 genes may play a role in the pathogenesis of some tumors. TRAIL can induce apoptosis on various continuous transformed cell lines and primary tumor cells, including several of hematopoietic origin, displaying minimal toxic effects on normal tissues. Because of the abilities of induction of both cytotoxic (apoptosis) and cytostatic (cell cycle perturbation) effects on the leukemic cells, TRAIL is currently considered as a potential(co) therapeutic drug against tumors.
Animals
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Apoptosis Regulatory Proteins
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Hematologic Neoplasms
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etiology
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therapy
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Humans
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Membrane Glycoproteins
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physiology
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Mutation
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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genetics
;
physiology
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Signal Transduction
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha
;
physiology
6.Therapy-Related Myeloid Neoplasms in 39 Korean Patients: A Single Institution Experience.
Hee Jae HUH ; Soo Hyun LEE ; Keon Hee YOO ; Ki Woong SUNG ; Hong Hoe KOO ; Kihyun KIM ; Jun Ho JANG ; Chulwon JUNG ; Sun Hee KIM ; Hee Jin KIM
Annals of Laboratory Medicine 2013;33(2):97-104
BACKGROUND: Therapy-related myeloid neoplasms (t-MN) occur as late complications of cytotoxic therapy. This study reviewed clinical and cytogenetic characteristics of patients with t-MN at a single institution in Korea. METHODS: The study subjects included 39 consecutive patients diagnosed with t-MN. Each subject's clinical history of previous diseases, treatments, and laboratory data was reviewed, including cytogenetics. The primary diagnosis was hematologic malignancy in 14 patients and solid tumor in 25 patients. RESULTS: Therapy-related acute myeloid leukemia (t-AML, 66.7%) was found to be more common than therapy-related myelodysplastic syndrome (t-MDS). Primary hematologic malignancies that were commonly implicated included mature B-cell neoplasm and acute leukemia. Breast cancer was the most common primary solid tumor. The mean time interval from cytotoxic therapy initiation to t-MN detection was 49 months. Chromosomal aberrations were observed in 35 patients, and loss of chromosome 5, 7, or both accounted for 41% of all cases. Balanced rearrangements occurred in 13 patients; these patients showed shorter latency intervals (mean, 38 months) than patients with loss of chromosome 5 or 7 (mean, 61 months). CONCLUSIONS: In this study, we determined the clinical and cytogenetic characteristics of Korean patients with t-MN. Although our results were generally consistent with those of previous reports, we found that t-MN resulting from de novo leukemia was common and that t-AML was more common than t-MDS at presentation. Multi-institutional studies involving a larger number of patients and additional parameters are required to investigate the epidemiology, genetic predisposition, and survival rate of t-MN in Korea.
Adolescent
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Adult
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Aged
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Antineoplastic Agents/*adverse effects/therapeutic use
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Asian Continental Ancestry Group
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Bone Marrow/pathology
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Breast Neoplasms/drug therapy/pathology/radiotherapy
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Child
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Child, Preschool
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Chromosome Aberrations
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Chromosomes, Human, Pair 5
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Chromosomes, Human, Pair 7
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Female
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Hematologic Neoplasms/drug therapy/pathology/radiotherapy
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Humans
;
Karyotyping
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Leukemia, Myeloid, Acute/*diagnosis/etiology/genetics
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Male
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Middle Aged
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Myelodysplastic Syndromes/*diagnosis/etiology/genetics
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Neoplasms, Second Primary/*diagnosis/etiology/genetics
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Republic of Korea
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Young Adult