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1.
Braz J Med Biol Res ; 52(6): e8424, 2019.
Article in English | MEDLINE | ID: mdl-31141090

ABSTRACT

Although rare, CALM/AF10 is a chromosomal rearrangement found in immature T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia, and mixed phenotype acute leukemia of T/myeloid lineages with poor prognosis. Moreover, this translocation is detected in 50% of T-ALL patients with gamma/delta T cell receptor rearrangement, frequently associated with low expression of transcription factor CCAAT/enhancer-binding protein alpha (CEBPA). However, the relevance of CEBPA low expression for CALM/AF10 leukemogenesis has not yet been evaluated. We generated double mutant mice, which express the Lck-CALM/AF10 fusion gene and are haploinsufficient for the Cebpa gene. To characterize the hematopoiesis, we quantified hematopoietic stem cells, myeloid progenitor cells, megakaryocyte-erythrocyte progenitor cells, common myeloid progenitor cells, and granulocyte-macrophage progenitor cells. No significant difference was detected in any of the progenitor subsets. Finally, we tested if Cebpa haploinsufficiency would lead to the expansion of Mac-1+/B220+/c-Kit+ cells proposed as the CALM/AF10 leukemic progenitor. Less than 1% of bone marrow cells expressed Mac-1, B220, and c-Kit with no significant difference between groups. Our results showed that the reduction of Cebpa gene expression in Lck-CALM/AF10 mice did not affect their hematopoiesis or induce leukemia. Our data corroborated previous studies suggesting that the CALM/AF10 leukemia-initiating cells are early progenitors with lymphoid/myeloid differentiating potential.


Subject(s)
CCAAT-Enhancer-Binding Protein-alpha/genetics , Haploinsufficiency/genetics , Hematopoiesis/genetics , Leukemia, Myeloid, Acute/genetics , Acute Disease , Animals , Flow Cytometry , Genotype , Mice , Mice, Transgenic , Phenotype , Transcription Factors/genetics , Translocation, Genetic/genetics
2.
Braz. j. med. biol. res ; 52(6): e8424, 2019. tab, graf
Article in English | LILACS | ID: biblio-1001535

ABSTRACT

Although rare, CALM/AF10 is a chromosomal rearrangement found in immature T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia, and mixed phenotype acute leukemia of T/myeloid lineages with poor prognosis. Moreover, this translocation is detected in 50% of T-ALL patients with gamma/delta T cell receptor rearrangement, frequently associated with low expression of transcription factor CCAAT/enhancer-binding protein alpha (CEBPA). However, the relevance of CEBPA low expression for CALM/AF10 leukemogenesis has not yet been evaluated. We generated double mutant mice, which express the Lck-CALM/AF10 fusion gene and are haploinsufficient for the Cebpa gene. To characterize the hematopoiesis, we quantified hematopoietic stem cells, myeloid progenitor cells, megakaryocyte-erythrocyte progenitor cells, common myeloid progenitor cells, and granulocyte-macrophage progenitor cells. No significant difference was detected in any of the progenitor subsets. Finally, we tested if Cebpa haploinsufficiency would lead to the expansion of Mac-1+/B220+/c-Kit+ cells proposed as the CALM/AF10 leukemic progenitor. Less than 1% of bone marrow cells expressed Mac-1, B220, and c-Kit with no significant difference between groups. Our results showed that the reduction of Cebpa gene expression in Lck-CALM/AF10 mice did not affect their hematopoiesis or induce leukemia. Our data corroborated previous studies suggesting that the CALM/AF10 leukemia-initiating cells are early progenitors with lymphoid/myeloid differentiating potential.


Subject(s)
Animals , Rabbits , Leukemia, Myeloid, Acute/genetics , CCAAT-Enhancer-Binding Protein-alpha/genetics , Haploinsufficiency/genetics , Hematopoiesis/genetics , Phenotype , Transcription Factors/genetics , Translocation, Genetic/genetics , Mice, Transgenic , Acute Disease , Flow Cytometry , Genotype
3.
Braz J Med Biol Res ; 50(5): e6019, 2017 Apr 13.
Article in English | MEDLINE | ID: mdl-28423121

ABSTRACT

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic clinical entity characterized by the proliferation of monoclonal B cells not meeting the diagnosis criteria for chronic lymphocytic leukemia (CLL). MBL may precede the development of CLL, but the molecular mechanisms responsible for disease progression and evolution are not completely known. Telomeres are usually short in CLL and their attrition may contribute to disease evolution. Here, we determined the telomere lengths of CD5+CD19+ cells in MBL, CLL, and healthy volunteers. Twenty-one CLL patients, 11 subjects with high-count MBL, and 6 with low-count MBL were enrolled. Two hundred and sixty-one healthy volunteers aged 0 to 88 years were studied as controls. After diagnosis confirmation, a flow cytometry CD19+CD5+-based cell sorting was performed for the study groups. Telomere length was determined by qPCR. Telomere length was similar in the 3 study groups but shorter in these groups compared to normal age-matched subjects that had been enrolled in a previous study from our group. These findings suggest that telomere shortening is an early event in CLL leukemogenesis.


Subject(s)
B-Lymphocytes/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Lymphocytosis/genetics , Lymphocytosis/pathology , Telomere Shortening/genetics , Age Factors , Aged , Aged, 80 and over , Case-Control Studies , Disease Progression , Female , Flow Cytometry , Genetic Markers , Humans , Lymphocyte Count , Male , Middle Aged , Reference Standards , Statistics, Nonparametric , Telomere/pathology
4.
Leukemia ; 26(3): 451-60, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21869839

ABSTRACT

The vitamin E derivative (+)α-tocopheryl succinate (α-TOS) exerts pro-apoptotic effects in a wide range of tumors and is well tolerated by normal tissues. Previous studies point to a mitochondrial involvement in the action mechanism; however, the early steps have not been fully elucidated. In a model of acute promyelocytic leukemia (APL) derived from hCG-PML-RARα transgenic mice, we demonstrated that α-TOS is as effective as arsenic trioxide or all-trans retinoic acid, the current gold standards of therapy. We also demonstrated that α-TOS induces an early dissipation of the mitochondrial membrane potential in APL cells and studies with isolated mitochondria revealed that this action may result from the inhibition of mitochondrial respiratory chain complex I. Moreover, α-TOS promoted accumulation of reactive oxygen species hours before mitochondrial cytochrome c release and caspases activation. Therefore, an in vivo antileukemic action and a novel mitochondrial target were revealed for α-TOS, as well as mitochondrial respiratory complex I was highlighted as potential target for anticancer therapy.


Subject(s)
Arsenicals/therapeutic use , Electron Transport Complex I/antagonists & inhibitors , Leukemia, Promyelocytic, Acute/drug therapy , Mitochondria/drug effects , Oxides/therapeutic use , Tretinoin/therapeutic use , alpha-Tocopherol/pharmacology , alpha-Tocopherol/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Apoptosis/drug effects , Arsenic Trioxide , Caspases/metabolism , Cell Line, Tumor , Cytochromes c/metabolism , Disease Models, Animal , Electron Transport Complex II/antagonists & inhibitors , Humans , Leukemia, Promyelocytic, Acute/mortality , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Transgenic , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Oncogene Proteins, Fusion/metabolism , Protein Stability/drug effects , Rats , Reactive Oxygen Species/metabolism , Transplantation, Isogeneic
5.
Biochim Biophys Acta ; 1798(9): 1714-23, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20488162

ABSTRACT

10-(Octyloxy) decyl-2-(trimethylammonium) ethyl phosphate (ODPC) is an alkylphospholipid that can interact with cell membranes because of its amphiphilic character. We describe here the interaction of ODPC with liposomes and its toxicity to leukemic cells with an ED-50 of 5.4, 5.6 and 2.9 microM for 72 h of treatment for inhibition of proliferation of NB4, U937 and K562 cell lines, respectively, and lack of toxicity to normal hematopoietic progenitor cells at concentrations up to 25 microM. The ED-50 for the non-malignant HEK-293 and primary human umbilical vein endothelial cells (HUVEC) was 63.4 and 60.7 microM, respectively. The critical micellar concentration (CMC) of ODPC was 200 microM. Dynamic light scattering indicated that dipalmitoylphosphatidylcholine (DPPC) liposome size was affected only above the CMC of ODPC. Differential calorimetric scanning (DCS) of liposomes indicated a critical transition temperature (T(c)) of 41.5 degrees C and an enthalpy (H) variation of 7.3 kcal mol(-1). The presence of 25 microM ODPC decreased T(c) and H to 39.3 degrees C and 4.7 kcal mol(-1), respectively. ODPC at 250 microM destabilized the liposomes (36.3 degrees C, 0.46 kcal mol(-1)). Kinetics of 5(6)-carboxyfluorescein (CF) leakage from different liposome systems indicated that the rate and extent of CF release depended on liposome composition and ODPC concentration and that above the CMC it was instantaneous. Overall, the data indicate that ODPC acts on in vitro membrane systems and leukemia cell lines at concentrations below its CMC, suggesting that it does not act as a detergent and that this effect is dependent on membrane composition.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Membrane/drug effects , Leukemia/drug therapy , Phospholipids/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Membrane Permeability/drug effects , Cell Survival/drug effects , Hematopoietic Stem Cells/drug effects , Humans , Leukemia/pathology , Liposomes , Micelles , Thermodynamics
6.
Braz J Med Biol Res ; 39(5): 615-20, 2006 May.
Article in English | MEDLINE | ID: mdl-16648899

ABSTRACT

Acute promyelocytic leukemia (APL) is characterized by the expansion of blasts that resemble morphologically promyelocytes and harbor a chromosomal translocation involving the retinoic acid receptor alpha (RARalpha) and the promyelocytic leukemia (PML) genes on chromosomes 17 and 15, respectively. The expression of the PML/RARalpha fusion gene is essential for APL genesis. In fact, transgenic mice (TM) expressing PML/RARalpha develop a form of leukemia that mimics the hematological findings of human APL. Leukemia is diagnosed after a long latency (approximately 12 months) during which no hematological abnormality is detected in peripheral blood (pre-leukemic phase). In humans, immunophenotypic analysis of APL blasts revealed distinct features; however, the precise immunophenotype of leukemic cells in the TM model has not been established. Our aim was to characterize the expression of myeloid antigens by leukemic cells from hCG-PML/RARalpha TM. In this study, TM (N = 12) developed leukemia at the mean age of 13.1 months. Morphological analysis of bone marrow revealed an increase of the percentage of immature myeloid cells in leukemic TM compared to pre-leukemic TM and wild-type controls (48.63 +/- 16.68, 10.83 +/- 8.11, 7.4 +/- 5.46%, respectively; P < 0.05). Flow cytometry analysis of bone marrow and spleen from leukemic TM identified the asynchronous co-expression of CD34, CD117, and CD11b. This abnormal phenotype was rarely detected prior to the diagnosis of leukemia and was present at similar frequencies in hematologically normal TM and wild-type controls of different ages. The present results demonstrate that, similarly to human APL, leukemic cells from hCG-PML/RARalpha TM present a specific immunophenotype.


Subject(s)
Antigens, CD/immunology , Leukemia, Myeloid, Acute/immunology , Leukemia, Promyelocytic, Acute/immunology , Oncogene Proteins, Fusion/immunology , Animals , Antigens, CD/genetics , Bone Marrow/immunology , Bone Marrow/pathology , Cathepsin G , Cathepsins , Flow Cytometry , Genotype , Immunophenotyping , Leukemia, Myeloid, Acute/genetics , Leukemia, Promyelocytic, Acute/genetics , Mice , Mice, Transgenic , Oncogene Proteins, Fusion/genetics , Serine Endopeptidases , Spleen/immunology , Spleen/pathology
7.
Braz. j. med. biol. res ; 39(5): 615-620, May 2006. tab
Article in English | LILACS | ID: lil-425793

ABSTRACT

Acute promyelocytic leukemia (APL) is characterized by the expansion of blasts that resemble morphologically promyelocytes and harbor a chromosomal translocation involving the retinoic acid receptor a (RARa) and the promyelocytic leukemia (PML) genes on chromosomes 17 and 15, respectively. The expression of the PML/RARa fusion gene is essential for APL genesis. In fact, transgenic mice (TM) expressing PML/RARa develop a form of leukemia that mimics the hematological findings of human APL. Leukemia is diagnosed after a long latency (approximately 12 months) during which no hematological abnormality is detected in peripheral blood (pre-leukemic phase). In humans, immunophenotypic analysis of APL blasts revealed distinct features; however, the precise immunophenotype of leukemic cells in the TM model has not been established. Our aim was to characterize the expression of myeloid antigens by leukemic cells from hCG-PML/RARa TM. In this study, TM (N = 12) developed leukemia at the mean age of 13.1 months. Morphological analysis of bone marrow revealed an increase of the percentage of immature myeloid cells in leukemic TM compared to pre-leukemic TM and wild-type controls (48.63 ± 16.68, 10.83 ± 8.11, 7.4 ± 5.46 percent, respectively; P < 0.05). Flow cytometry analysis of bone marrow and spleen from leukemic TM identified the asynchronous co-expression of CD34, CD117, and CD11b. This abnormal phenotype was rarely detected prior to the diagnosis of leukemia and was present at similar frequencies in hematologically normal TM and wild-type controls of different ages. The present results demonstrate that, similarly to human APL, leukemic cells from hCG-PML/RARa TM present a specific immunophenotype.


Subject(s)
Animals , Mice , Antigens, CD/immunology , Leukemia, Myeloid, Acute/immunology , Leukemia, Promyelocytic, Acute/immunology , Oncogene Proteins, Fusion/immunology , Antigens, CD/genetics , Bone Marrow/immunology , Bone Marrow/pathology , Cathepsins , Flow Cytometry , Genotype , Immunophenotyping , Leukemia, Myeloid, Acute/genetics , Leukemia, Promyelocytic, Acute/genetics , Mice, Transgenic , Oncogene Proteins, Fusion/genetics , Serine Endopeptidases , Spleen/immunology , Spleen/pathology
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