BACKGROUND: Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown. METHODS: Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca 2+ -related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance. RESULTS: Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca 2+ is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments. CONCLUSIONS Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy.
Animals ; Humans ; Mice ; Apoptosis ; Bone Marrow Cells ; Cell Communication ; Connexin 43/genetics* ; Gap Junctions/metabolism* ; Imatinib Mesylate/therapeutic use* ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology* ; Mesenchymal Stem Cells/metabolism* ; Tumor Microenvironment ; Calcium/metabolism*

No abstract available.
Bone Marrow/pathology ; Chromosomes, Human, Pair 12 ; Chromosomes, Human, Pair 9 ; Core Binding Factor Alpha 2 Subunit/*genetics ; DNA/metabolism ; Gene Rearrangement ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis/*genetics ; Male ; Middle Aged ; Oncogene Proteins, Fusion/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Translocation, Genetic

No abstract available.
Aged, 80 and over ; Base Sequence ; Bone Marrow/pathology ; DNA/chemistry/metabolism ; Female ; Fusion Proteins, bcr-abl/*genetics ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis/*genetics ; Multiplex Polymerase Chain Reaction ; Protein Isoforms/genetics ; Sequence Analysis, DNA

No abstract available.
Base Sequence ; Bone Marrow/pathology ; Fusion Proteins, bcr-abl/*genetics ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis/*genetics ; Male ; Middle Aged ; Real-Time Polymerase Chain Reaction

No abstract available.
Aged ; Antineoplastic Agents/therapeutic use ; Bone Marrow/pathology ; Fusion Proteins, bcr-abl/genetics/metabolism ; Humans ; Imatinib Mesylate/therapeutic use ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications/*diagnosis/drug therapy ; Leukocyte Count ; Male ; Multiple Myeloma/complications/*diagnosis/drug therapy ; Platelet Count ; Polymerase Chain Reaction ; Thrombocytosis/etiology

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a chromosome translocation that generates the Bcr-Abl oncogene encoding a constitutive kinase activity. Despite remarkable success in controlling CML at chronic phase by Bcr-Abl tyrosine kinase inhibitors (TKIs), a significant proportion of CML patients treated with TKIs develop drug resistance due to the inability of TKIs to kill leukemia stem cells (LSCs) that are responsible for initiation, drug resistance, and relapse of CML. Therefore, there is an urgent need for more potent and safer therapies against leukemia stem cells for curing CML. A number of LSC-associated targets and corresponding signaling pathways, including CaMKII-γ, a critical molecular switch for co-activating multiple LSC-associated signaling pathways, have been identified over the past decades and various small inhibitors targeting LSC are also under development. Increasing evidence shows that leukemia stem cells are the root of CML and targeting LSC may offer a curable treatment option for CML patients. This review summarizes the molecular biology of LSC and its-associated targets, and the potential clinical application in chronic myeloid leukemia.
Animals ; Chemokines ; metabolism ; Epigenesis, Genetic ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; metabolism ; pathology ; Neoplastic Stem Cells ; metabolism ; pathology ; Transcription Factors ; metabolism ; Tumor Microenvironment

No abstract available.
Antineoplastic Agents/*therapeutic use ; Benzamides/*therapeutic use ; Central Nervous System Neoplasms/*diagnosis ; Fusion Proteins, bcr-abl/genetics ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy ; Leukocytes/metabolism/pathology ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Piperazines/*therapeutic use ; Pyrimidines/*therapeutic use

No abstract available.
Base Sequence ; Benzamides/therapeutic use ; Bone Marrow/pathology ; Female ; Fusion Proteins, bcr-abl/*genetics ; Humans ; Karyotyping ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/*genetics ; Middle Aged ; Philadelphia Chromosome ; Piperazines/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; Pyrimidines/therapeutic use ; Sequence Analysis, DNA ; Thiazoles/therapeutic use ; Translocation, Genetic

No abstract available.
Adult ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Benzamides/therapeutic use ; Bone Marrow Examination ; Chemoradiotherapy ; Cyclophosphamide/administration & dosage ; Doxorubicin/administration & dosage ; Humans ; Karyotyping ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*diagnosis/drug therapy/genetics/pathology ; Lymphoma, Large B-Cell, Diffuse/*diagnosis/pathology/therapy ; Male ; *Neoplasms, Second Primary ; Piperazines/therapeutic use ; Positron-Emission Tomography ; Prednisolone/administration & dosage ; Protein Kinase Inhibitors/therapeutic use ; Pyrimidines/therapeutic use ; Time Factors ; Tomography, X-Ray Computed ; Treatment Outcome ; Vincristine/administration & dosage ; Whole Body Imaging/methods

No abstract available.
Acute Disease ; Child ; Chromosomes, Human, Pair 22 ; Chromosomes, Human, Pair 9 ; Female ; Fusion Proteins, bcr-abl/genetics ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia/*genetics/pathology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/pathology ; Male ; Middle Aged ; Phenotype ; *Translocation, Genetic