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1.
Leuk Res ; 37(1): 93-101, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23099235

ABSTRACT

Since BCR-ABL plays an essential role in the growth factor-independent proliferation of Philadelphia chromosome (Ph)+ leukemia cells, imatinib treatment of Ph+ leukemia cells inactivates signaling pathways of BCR-ABL, and subsequent addition of growth factors (GFs) could restore the signaling pathways without reactivating BCR-ABL. Here we demonstrated that non-lymphoid Ph+ leukemia cell lines responded to diverse GFs depending on their immunophenotype and gene expression of transcription factors and GF receptors, while lymphoid Ph+ leukemia cell lines restrictively responded to flit3 ligand and interleukin-7, suggesting that GF sensitivity of imatinib-treated Ph+ leukemia cells could be powerful for specifying their distinctive lineage.


Subject(s)
Antineoplastic Agents/pharmacology , Intercellular Signaling Peptides and Proteins/pharmacology , Leukemia/drug therapy , Philadelphia Chromosome , Piperazines/pharmacology , Pyrimidines/pharmacology , Benzamides , Cell Line, Tumor , Cell Proliferation/drug effects , Granulocyte Colony-Stimulating Factor/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Humans , Imatinib Mesylate , Interleukin-6/pharmacology , Leukemia/genetics , Leukemia/pathology
2.
Leuk Res ; 35(7): 940-9, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21466892

ABSTRACT

Philadelphia-chromosome (Ph1)-positive leukemia cells frequently express death receptors DR4/DR5 for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and show high TRAIL-sensitivity. It has been reported that imatinib damaged cardiomyocytes by triggering endoplasmic reticulum (ER) stress and that ER stress inducers intensified TRAIL-sensitivity of some cancer cells by upregulating DR4/DR5 expression. In fact, ER stress inducers enhanced TRAIL-sensitivity of Ph1-positive leukemia cells by upregulating DR4/DR5 expression. In contrast, imatinib did not induce ER stress responses and unexpectedly downregulated DR4/DR5 expression, indicating that sensitization of Ph1-positive leukemia cells to TRAIL-mediated cellular immunity by imatinib through upregulation of DR4/DR5 expression is unlikely.


Subject(s)
Apoptosis/drug effects , Endoplasmic Reticulum/drug effects , Leukemia/pathology , Philadelphia Chromosome , Piperazines/pharmacology , Pyrimidines/pharmacology , TNF-Related Apoptosis-Inducing Ligand/metabolism , Thapsigargin/pharmacology , Tunicamycin/pharmacology , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Benzamides , Blotting, Western , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/pathology , Enzyme Inhibitors/pharmacology , Humans , Imatinib Mesylate , Leukemia/drug therapy , Leukemia/metabolism , RNA, Messenger/genetics , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Reverse Transcriptase Polymerase Chain Reaction , TNF-Related Apoptosis-Inducing Ligand/genetics , Tumor Cells, Cultured
3.
Exp Hematol ; 38(10): 885-95, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20670671

ABSTRACT

OBJECTIVE: Cytotoxic ligands are involved in tumor immunity and graft-vs.-leukemia effect after allogeneic stem cell transplantation for leukemia. To clarify the susceptibility of T-cell acute lymphoblastic leukemia (T-ALL) to tumor immunity, sensitivity to recombinant human soluble Fas ligand (rhsFasL) and tumor necrosis factor-related apoptosis-inducing ligand (rhsTRAIL) was determined. MATERIALS AND METHODS: Sensitivity to rhsFasL and rhsTRAIL and cell surface expression of their receptors were tested in T-ALL cell lines (n = 7) and patients' samples (n = 17) and compared with those in B-precursor ALL cell lines (n = 30). Expression of components of the death-inducing signaling complex and the TRAIL receptor genes (DR4/DR5), and the methylation status and promoter activity of the DR4/DR5 gene were tested in T-ALL cell lines. RESULTS: T-ALL cell lines showed higher level of Fas expression and higher sensitivity to rhsFasL than did B-precursor ALL cell lines. Despite comparable expression of components of death-inducing signaling complex, cell lines and patients' samples of T-ALL showed TRAIL-resistance associated with low cell surface expression of DR4/DR5. Gene expression of DR4/DR5 in T-ALL cell lines was significantly lower than that in B-precursor ALL cell lines, and the methylation status of the gene promoter in T-ALL cell lines was associated with the gene expression level at least for DR4. The demethylating agent, 5-aza 2'deoxycytidine, upregulated the gene expression of DR4/DR5, but was insufficient for their surface expression due to low basal promoter activity. CONCLUSIONS: In contrast to higher sensitivity to FasL, T-ALL showed resistance to TRAIL, which might be responsible for resistance to TRAIL-mediated cellular immunity.


Subject(s)
Apoptosis/drug effects , Cell Proliferation/drug effects , Fas Ligand Protein/pharmacology , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Cell Line, Tumor , Cells, Cultured , DNA Methylation/drug effects , Dose-Response Relationship, Drug , Drug Resistance , Flow Cytometry , Gene Expression/drug effects , Humans , Immunoblotting , Jurkat Cells , Luciferases/genetics , Luciferases/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Promoter Regions, Genetic/genetics , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Reverse Transcriptase Polymerase Chain Reaction , fas Receptor/metabolism
4.
Blood ; 116(6): 962-70, 2010 Aug 12.
Article in English | MEDLINE | ID: mdl-20519628

ABSTRACT

LMO2, a critical transcription regulator of hematopoiesis, is involved in human T-cell leukemia. The binding site of proline and acidic amino acid-rich protein (PAR) transcription factors in the promoter of the LMO2 gene plays a central role in hematopoietic-specific expression. E2A-HLF fusion derived from t(17;19) in B-precursor acute lymphoblastic leukemia (ALL) has the transactivation domain of E2A and the basic region/leucine zipper domain of HLF, which is a PAR transcription factor, raising the possibility that E2A-HLF aberrantly induces LMO2 expression. We here demonstrate that cell lines and a primary sample of t(17;19)-ALL expressed LMO2 at significantly higher levels than other B-precursor ALLs did. Transfection of E2A-HLF into a non-t(17;19) B-precursor ALL cell line induced LMO2 gene expression that was dependent on the DNA-binding and transactivation activities of E2A-HLF. The PAR site in the LMO2 gene promoter was critical for E2A-HLF-induced LMO2 expression. Gene silencing of LMO2 in a t(17;19)-ALL cell line by short hairpin RNA induced apoptotic cell death. These observations indicated that E2A-HLF promotes cell survival of t(17;19)-ALL cells by aberrantly up-regulating LMO2 expression. LMO2 could be a target for a new therapeutic modality for extremely chemo-resistant t(17;19)-ALL.


Subject(s)
DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Metalloproteins/genetics , Oncogene Proteins, Fusion/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cells, B-Lymphoid/physiology , Transcription Factors/metabolism , Translocation, Genetic , Adaptor Proteins, Signal Transducing , Apoptosis/physiology , Blotting, Western , Cell Line, Tumor , Chromosomes, Human, Pair 17 , Chromosomes, Human, Pair 19 , Fetal Blood/cytology , Gene Expression Regulation, Leukemic , Humans , LIM Domain Proteins , Lentivirus/genetics , Metalloproteins/metabolism , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor Cells, B-Lymphoid/cytology , Promoter Regions, Genetic/physiology , Proto-Oncogene Proteins , RNA, Small Interfering , Transcription Factors/genetics , Up-Regulation/genetics
5.
Rinsho Ketsueki ; 51(2): 132-7, 2010 Feb.
Article in Japanese | MEDLINE | ID: mdl-20379105

ABSTRACT

We report a patient who developed multiple serositis during chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation from a non-inherited maternal antigen (NIMA) -complementary sibling donor. The patient was a 9-year-old boy with myelodysplastic syndrome, who urgently underwent bone marrow transplantation from his NIMA-complementary HLA two-locus-mismatched sister following graft failure of cord blood transplantation. Engraftment was successfully confirmed and no acute GVHD developed. After withdrawal of tacrolimus to prevent recurrent viral infection, he developed pleural effusion, ascites and edema approximately 6 months after transplantation. His clinical symptoms were resolved by methylprednisolone pulse therapy, but he subsequently progressed to develop pericardial effusion, pneumothorax and truncal panniculitis. Pleural and pericardial effusion contained numerous lymphocytes, which gradually subsided with continuous drainage. His symptoms were thereafter controlled by the addition of mycophenolate mofetil (MMF) administration, and his current performance status is almost perfect by the administration of prednisolone (5 mg/day) and MMF at 6 years after transplantation. Although multiple serositis associated with GVHD is known to have a poor prognosis, the multiple symptoms of this patient improved gradually, probably owing to a lack of acute GVHD and the effect of MMF.


Subject(s)
Bone Marrow Transplantation , Graft vs Host Disease/therapy , Myelodysplastic Syndromes/therapy , Serositis/therapy , Siblings , Tissue Donors , Adolescent , Child , Chronic Disease , Drainage , Female , Graft vs Host Disease/etiology , HLA Antigens , Histocompatibility , Humans , Immunosuppressive Agents/administration & dosage , Male , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/analogs & derivatives , Serositis/etiology , Treatment Outcome
6.
Cancer Res ; 67(20): 9852-61, 2007 Oct 15.
Article in English | MEDLINE | ID: mdl-17942916

ABSTRACT

Fms-like tyrosine kinase 3 (FLT3) is highly expressed in acute lymphoblastic leukemia with the mixed-lineage leukemia (MLL) gene rearrangement refractory to chemotherapy. We examined the biological effect of FLT3-ligand (FL) on 18 B-precursor leukemic cell lines with variable karyotypic abnormalities, and found that nine of nine MLL-rearranged cell lines with wild-type FLT3, in contrast to other leukemic cell lines, are significantly inhibited in their proliferation in a dose-dependent manner by FL. This inhibition was due to induction of the G0-G1 arrest. A marked up-regulation of p27 by suppression of its protein degradation and an abrogation of constitutive signal transducers and activators of transcription 5 phosphorylation were revealed in arrested leukemia cells after FL stimulation. Importantly, FL treatment rendered not only cell lines but also primary leukemia cells with MLL rearrangement resistant to chemotherapeutic agents. MLL-rearranged leukemia cells adhering to the bone marrow stromal cell line, which expresses FL as the membrane-bound form, were induced to quiescent state resistant to chemotherapeutic agents, but their chemosensitivity was significantly restored in the presence of neutralizing anti-FL antibody. The FL/FLT3 interaction between leukemia cells and bone marrow stromal cells expressing FL at high levels should contribute, at least in part, to persistent minimal-residual disease of MLL-rearranged leukemia in bone marrow.


Subject(s)
Membrane Proteins/pharmacology , Myeloid-Lymphoid Leukemia Protein/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Apoptosis/drug effects , Bone Marrow Cells/pathology , Cell Cycle/drug effects , Cell Growth Processes/drug effects , Cell Line, Tumor , Child, Preschool , Cyclin-Dependent Kinase Inhibitor p27 , Dose-Response Relationship, Drug , Female , Gene Rearrangement , Histone-Lysine N-Methyltransferase , Humans , Infant , Infant, Newborn , Intracellular Signaling Peptides and Proteins/metabolism , Male , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Proto-Oncogene Proteins c-akt/metabolism , STAT5 Transcription Factor/metabolism , Stromal Cells/pathology , Up-Regulation/drug effects , fms-Like Tyrosine Kinase 3/metabolism
7.
Br J Haematol ; 139(2): 280-3, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17764467

ABSTRACT

Neutrophil-specific antigen (NA) expression on neutrophils was analysed in 18 Japanese children before and after allogeneic stem cell transplantation (allo-SCT) with myeloablative regimen. Donor-recipient NA-incompatibility was present in one of eight NA1/NA2 heterozygous patients and eight of 10 NA1/NA1 or NA2/NA2 homozygous patients. After allo-SCTs from NA-incompatible donors, a neutrophil recipient-to-donor conversion was confirmed in all cases. Conversion to donor NA type was complete before the absolute neutrophil count reached 0.1 x 10(9)/l. These observations indicate that flow cytometric analysis of NA antigens is a simple and useful method for monitoring neutrophil engraftment in NA-incompatible allo-SCT.


Subject(s)
Isoantigens/analysis , Neutrophils/transplantation , Stem Cell Transplantation/methods , Antibodies, Monoclonal/immunology , Biomarkers/analysis , Child , Flow Cytometry , Graft Survival , Humans , Neutrophils/metabolism , Time , Transplantation, Homologous
9.
Int J Hematol ; 82(2): 132-6, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16146845

ABSTRACT

Senescent erythrocytes undergo a loss of phospholipid asymmetry in the plasma membrane and are removed from the circulation by phagocytosis.To examine the loss of phospholipid asymmetry in mature erythrocytes after chemotherapy, we monitored phosphatidylserine (PS)-exposing erythrocytes by using flow cytometry to detect annexin V-bound erythrocytes in the circulation of acute lymphoblastic leukemia patients after consolidation chemotherapy. Both the percentage and the absolute number of annexin V-positive erythrocytes gradually increased immediately after chemotherapy. This result paralleled the change in the serum levels of bilirubin, suggesting a direct induction of PS-externalization in mature erythrocytes and a subsequent increase in erythrocyte clearance by splenic macrophages. The PS-exposing erythrocyte counts showed negative correlations to platelet and reticulocyte counts, which reflect the hematopoietic potential in the bone marrow. This result suggests that bone marrow suppression could be responsible for the enlarged senescent population in the circulation. Moreover, PS-exposing erythrocytes in the circulation remained at relatively high levels even after the serum level of bilirubin normalized, indicating that the decreased clearance of senescent erythrocytes as a result of impaired phagocytosis following bone marrow suppression might also be involved in the increase in PS-exposing erythrocytes in the circulation late after chemotherapy.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Cytarabine/administration & dosage , Erythrocyte Membrane/metabolism , Phospholipids/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Annexin A5/metabolism , Bone Marrow/metabolism , Bone Marrow/pathology , Cellular Senescence/drug effects , Erythrocyte Membrane/pathology , Erythropoiesis/drug effects , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
10.
Rinsho Ketsueki ; 45(4): 297-303, 2004 Apr.
Article in Japanese | MEDLINE | ID: mdl-15168445

ABSTRACT

The effect and safety of combination prophylaxis for hepatic veno-occlusive disease (VOD) following stem cell transplantation (SCT) was retrospectively evaluated in a total of 53 children who survived until day 30. Prophylaxis was started on the day before conditioning, and heparin (10 unit/kg/hr) alone was used in 6 patients, PGE1 (5 ng/kg/min) plus heparin plus PTX (200 mg/day) in 17 patients, lipo-PGE1 (0.5 ng/kg/min) plus heparin plus PTX in 7 patients, and lipo-PGE1 plus heparin in 23 patients. Diagnosis of VOD was made based on McDonald's criteria in 5 cases (9.4%), but not on Jones' criteria. No statistically significant difference was observed in the incidence of VOD among each prophylaxis group. The degree of VOD was mild in all of 5 cases, and all recovered with continuation of the prophylactic procedure. Each prophylactic procedure was performed without any significant adverse effect except for seizure induced by lipo-PGE1 in one patient with Lennox syndrome. Since both the incidence and fatality rate of VOD in children undergoing SCT are approximately 20% according to most of the previous reports, the present study suggests the effectiveness of combination prophylaxis.


Subject(s)
Alprostadil/administration & dosage , Hematopoietic Stem Cell Transplantation , Heparin/administration & dosage , Hepatic Veno-Occlusive Disease/prevention & control , Adolescent , Child , Drug Therapy, Combination , Female , Humans , Male , Postoperative Complications/prevention & control , Retrospective Studies
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