[Bleeding due to acquired factor V inhibitor successfully treated with platelet transfusion during treatment for recurrent prostate squamous cell carcinoma].

A 78-year-old man with prostate squamous cell carcinoma recurrence in his pelvis was admitted to our hospital. Rectal obstruction led to creation of an artificial anus on the transverse colon. Then, docetaxel and radiation therapies were started.

Establishment and characterization of a novel vincristine-resistant diffuse large B-cell lymphoma cell line containing the 8q24 homogeneously staining region.

Chromosome band 8q24 is the most frequently amplified locus in various types of cancers. has been identified as the primary oncogene at the 8q24 locus, whereas a long noncoding gene, , which lies adjacent to , has recently emerged as another potential oncogenic regulator at this position. In this study, we established and characterized a novel cell line, AMU-ML2, from a patient with diffuse large B-cell lymphoma (DLBCL), displaying homogeneously staining regions at the 8q24 locus.

Feasibility of the imatinib stop study in the Japanese clinical setting: delightedly overcome CML expert stop TKI trial (DOMEST Trial).

Background: Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs).

Methods: A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.

Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment.

Introduction: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective.

Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells.

Leukemia cells in the bone marrow must meet the biochemical demands of increased cell proliferation and also survive by continually adapting to fluctuations in nutrient and oxygen availability. Thus, targeting metabolic abnormalities in leukemia cells located in the bone marrow is a novel therapeutic approach. In this study, we investigated the metabolic role of bone marrow adipocytes in supporting the growth of leukemic blasts.

Overexpression of salivary-type amylase reduces the sensitivity to bortezomib in multiple myeloma cells.

Amylase-producing myeloma exhibits refractoriness to chemotherapy and a dismal prognosis. In this study, we established a human myeloma cell line, 8226/AMY1, in which a lentivirally transfected AMY1 gene was stably expressed and explored its biological characteristics. 8226/AMY1 showed a survival advantage over mock control when treated with dexamethasone, bortezomib, and lenalidomide in vitro partly through inhibition of apoptosis induced by these reagents.

Importance of glutamine metabolism in leukemia cells by energy production through TCA cycle and by redox homeostasis.

Some cancer cells depend on glutamine despite of pronounced glycolysis. We examined the glutamine metabolism in leukemia cells, and found that HL-60 cells most depended on glutamine in the 4 acute myelogenous leukemia (AML) cell lines examined: growth of HL-60 cells was most suppressed by glutamine deprivation and by inhibition of glutaminolysis, which was rescued by tricarboxylic acid (TCA) cycle intermediate, oxaloacetic acid. Glutamine is also involved in antioxidant defense function by increasing glutathione.

Adaptation of leukemia cells to hypoxic condition through switching the energy metabolism or avoiding the oxidative stress.

Background: Like normal hematopoietic stem cells, leukemia cells proliferate in bone marrow, where oxygen supply is limited. However, the growth and energy metabolism of leukemia cells under hypoxia have not been well understood. Although it has been known that reactive oxygen species (ROS) is generated under hypoxic conditions, normal and leukemia stem cells were characterized by relatively low levels of ROS.

Class IA PI3K inhibition inhibits cell growth and proliferation in mantle cell lymphoma.

Background/aims: Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway preferentially occurs in aggressive blastoid variants of mantle cell lymphoma (MCL) and is implicated in the pathogenesis of this disease. In this study, we investigated the role of PI3K isoforms on proliferation of aggressive MCL cells.

Methods: The changes in cell viability, cell cycle distribution and apoptosis induction by the PI3K isoform-selective inhibitors were evaluated.

PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment.

Unlabelled: Both phosphatidylinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling and antiapoptotic Bcl-2 family members are critical for survival of acute myeloid leukemia (AML) cells. Here, we demonstrate the antileukemic effects of simultaneous inhibition of PI3K by the selective class I PI3K inhibitor GDC-0941 and of Bcl-2 family members by the BH3 mimetic ABT-737 in the context of the bone marrow microenvironment, where hypoxia and interactions with bone marrow stromal cells promote AML cell survival and chemoresistance. The combination of GDC-0941 and ABT-737 profoundly downregulated antiapoptotic Mcl-1 expression levels, activated BAX, and induced mitochondrial apoptosis in AML cells co-cultured with bone marrow stromal cells under hypoxic conditions.

TGF-β-Neutralizing Antibody 1D11 Enhances Cytarabine-Induced Apoptosis in AML Cells in the Bone Marrow Microenvironment.

Hypoxia and interactions with bone marrow (BM) stromal cells have emerged as essential components of the leukemic BM microenvironment in promoting leukemia cell survival and chemoresistance. High levels of transforming growth factor beta 1 (TGFβ1) produced by BM stromal cells in the BM niche regulate cell proliferation, survival, and apoptosis, depending on the cellular context. Exogenous TGFβ1 induced accumulation of acute myeloid leukemia (AML) cells in a quiescent G0 state, which was further facilitated by the co-culture with BM-derived mesenchymal stem cells (MSCs).

Growth of xenotransplanted leukemia cells is influenced by diet nutrients and is attenuated with 2-deoxyglucose.

We examined the effects of diet nutrients on xenotransplanted leukemia cells, THP-1 or NB4. THP-1 tumors showed more growth when fed with high fat diet, while NB4 tumors grew more with high carbohydrate diet. Then, administration of 2-deoxyglucose (a glycolysis inhibitor) showed a significant antitumor effect on both tumors: NB4 tumor showed large necrotic areas, while THP-1 tumor did not, but had augmented expression of enzymes for fatty acid oxidation.

Leukemia cells demonstrate a different metabolic perturbation provoked by 2-deoxyglucose.

The shift in energy metabolism from oxidative phosphorylation to glycolysis can serve as a target for the inhibition of cancer growth. Here, we examined the metabolic changes induced by 2-deoxyglucose (2-DG), a glycolysis inhibitor, in leukemia cells by metabolome analysis. NB4 cells mainly utilized glucose as an energy source by glycolysis and oxidative phosphorylation in mitochondria, since metabolites in the glycolytic pathway and in the tricarboxylic acid (TCA) cycle were significantly decreased by 2-DG.

Establishment of a novel human myeloid leukemia cell line, AMU-AML1, carrying t(12;22)(p13;q11) without chimeric MN1-TEL and with high expression of MN1.

In this study, we established and analyzed a novel human myeloid leukemia cell line, AMU-AML1, from a patient with acute myeloid leukemia with multilineage dysplasia before the initiation of chemotherapy. AMU-AML1 cells were positive for CD13, CD33, CD117, and HLA-DR by flow cytometry analysis and showed a single chromosomal abnormality, 46, XY, t(12;22)(p13;q11.2), by G-banding and spectral karyotyping.

Energy metabolism of leukemia cells: glycolysis versus oxidative phosphorylation.

For generation of energy, cancer cells utilize glycolysis more vigorously than oxidative phosphorylation in mitochondria (Warburg effect). We examined the energy metabolism of four leukemia cell lines by using glycolysis inhibitor, 2-deoxy-d-glucose (2-DG) and inhibitor of oxidative phosphorylation, oligomycin. NB4 was relatively sensitive to 2-DG (IC(50): 5.

Cyclin-dependent kinase 1 inhibitor RO-3306 enhances p53-mediated Bax activation and mitochondrial apoptosis in AML.

Cyclin-dependent kinase (CDK) 1 and the murine double minute 2 homolog (MDM2)-p53 interaction are potential therapeutic targets in cancer, and their inhibition has been reported to be more proapoptotic in malignant cells compared to normal cells. We investigated the effect of CDK1 inhibition on p53 signaling after simultaneous dual blockade using the CDK1 inhibitor RO-3306 and the MDM2 inhibitor Nutlin-3 in AML. Treatment of growing AML cells with RO-3306 induced G2/M-phase cell cycle arrest and apoptosis in a dose- and time-dependent manner.

Growth inhibition of AML cells with specific chromosome abnormalities by monoclonal antibodies to receptors for vascular endothelial growth factor.

By using neutralizing monoclonal antibodies to vascular endothelial growth factor receptor type 1 (VEGFR1) and VEGFR2, we have shown that acute myelogenous leukemia (AML) cells with specific chromosome abnormalities are dependent on VEGF/VEGFR system. AML with t(8;21) is the most dependent subtype on VEGF with both VEGFR1 and VEGFR2. t(15;17)AML cells depend on VEGF with VEGFR1.

t(8;21) acute myeloid leukaemia cells are dependent on vascular endothelial growth factor (VEGF)/VEGF receptor type2 pathway and phosphorylation of Akt.

Several anti-angiogenic drugs have recently been clinically tested for haematological malignancies. To improve the efficacy of molecular target therapy against angiogenic molecules in acute myeloid leukaemia (AML), we examined the dependency of AML cells on the vascular endothelial growth factor (VEGF)/VEGF receptor type2 (VEGFR2) system by using VEGFR2 kinase inhibitor. Nineteen patient AML samples were cultured with or without VEGFR2 kinase inhibitor.

Low p53 expression of acute myelocytic leukemia cells with t(8;21) chromosome abnormality: association with low p14(ARF) expression.

In this study, the mRNA expression of p14(ARF) in t(8;21)AML cells was found to be significantly lower than acute myelocytic leukemia (AML) cells without t(8;21) chromosome abnormality, which was concordant with previous observation by Linggi et al. that AML1-MTG8 represses the transcription of p14(ARF). Although p53 mRNA expression level of t(8;21)AML cells was not low, p53 protein expression was reduced in t(8;21)AML cells.

Placenta growth factor stimulates the growth of Philadelphia chromosome positive acute lymphoblastic leukemia cells by both autocrine and paracrine pathways.

Vascular endothelial growth factor (VEGF) and its associated molecule, placenta growth factor (PlGF) are now known to support normal hematopoiesis, and leukemia cell growth. In this study, expression of VEGF and PlGF in acute lymphoblastic leukemia (ALL) cells was examined by real time reverse transcription-polymerase chain reaction in 20 patient samples. Expression of PlGF was more intense in Philadelphia chromosome positive (Ph(+)) ALL than in Ph(-) ALL cases.

MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy.

Although TP53 mutations are rare in acute myeloid leukemia (AML), inactivation of wild-type p53 protein frequently occurs through overexpression of its negative regulator MDM2 (murine double minute 2). Recently, small-molecule antagonists of MDM2, Nutlins, have been developed that inhibit the p53-MDM2 interaction and activate p53 signaling. Here, we study the effects of p53 activation by Nutlin-3 in AML cells.

Autocrine pathway of angiopoietins-Tie2 system in AML cells: association with phosphatidyl-inositol 3 kinase.

Hematopoietic cells and endothelial cells are mutually correlated in their development and growth. Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and angiopoietins (Angs), are thought to be associated with leukemia cell growth. In this study, we examined if the Angs-Tie2 autocrine pathway works in primary AML cells or not by using soluble Tie2-Fc, which inhibits Angs from binding to Tie2 receptor.

Acute promyelocytic leukemia with drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection.

We report a case of acute promyelocytic leukemia (APL) with drug-induced hypersensitivity syndrome associated with Epstein-Barr virus (EBV) infection. A 33-year-old woman was admitted because of APL. After complete remission was obtained with the use of all-trans retinoic acid (ATRA), intensive chemotherapy was administered.

Aplastic anaemia associated with a Philadelphia chromosome and monosomy 7 during immunosuppressive therapy.

We describe a patient who presented with aplastic anaemia associated with the Philadelphia (Ph1) chromosome during immunosuppressive therapy and who subsequently developed myelodysplastic syndrome (MDS) with monosomy 7. Initially the patient had hypocellular fatty marrow without leukaemic blasts or dysplastic features. Chromosome analysis showed 46, XY, t(9;22)(q34;q11) during immunosuppressive therapy, but no leukaemic transformation was detected.