Leukemia Research and Treatment http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. A Novel Cryptic Three-Way Translocation t(2;9;18)(p23.2;p21.3;q21.33) with Deletion of Tumor Suppressor Genes in 9p21.3 and 13q14 in a T-Cell Acute Lymphoblastic Leukemia Wed, 08 Oct 2014 11:51:06 +0000 http://www.hindawi.com/journals/lrt/2014/357123/ Acute leukemia often presents with pure chromosomal resolution; thus, aberrations may not be detected by banding cytogenetics. Here, a case of 26-year-old male diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and a normal karyotype after standard GTG-banding was studied retrospectively in detail by molecular cytogenetic and molecular approaches. Besides fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and high resolution array-comparative genomic hybridization (aCGH) were applied. Thus, cryptic chromosomal aberrations not observed before were detected: three chromosomes were involved in a cytogenetically balanced occurring translocation t(2;9;18)(p23.2;p21.3;q21.33). Besides a translocation t(10;14)(q24;q11) was identified, an aberration known to be common in T-ALL. Due to the three-way translocation deletion of tumor suppressor genes CDKN2A/INK4A/p16, CDKN2B/INK4B/p15, and MTAP/ARF/p14 in 9p21.3 took place. Additionally RB1 in 13q14 was deleted. This patient, considered to have a normal karyotype after low resolution banding cytogenetics, was treated according to general protocol of anticancer therapy (ALL-BFM 95). Moneeb A. K. Othman, Martina Rincic, Joana B. Melo, Isabel M. Carreira, Eyad Alhourani, Friederike Hunstig, Anita Glaser, and Thomas Liehr Copyright © 2014 Moneeb A. K. Othman et al. All rights reserved. Postinduction Supportive Care of Pediatric Acute Myelocytic Leukemia: Should Patients be Kept in the Hospital? Mon, 29 Sep 2014 09:25:55 +0000 http://www.hindawi.com/journals/lrt/2014/592379/ Children with AML become profoundly neutropenic while they undergo remission induction chemotherapy. It is unknown whether these children should be kept in the hospital while they are severely neutropenic to prevent life-threatening complications associated with neutropenia and reduce fatality. We at our institution routinely discharge patients after completing remission induction chemotherapy in the presence of profound neutropenia, unless it is clinically contraindicated. We reviewed all AML patients who were consecutively treated at our hospital from 1989 to 2011. Thirteen patients were electively discharged after completion of induction I chemotherapy. Of the 13, 4 died due to relapse or complications of stem cell transplants (not due to neutropenia related complications). Another eight are long term survivors. In this very small series, discharge from the hospital even though patients were severely neutropenic did not adversely affect the survival. Susumu Inoue, Isra’a Khan, Rao Mushtaq, Dawn Carson, Elna Saah, and Nkechi Onwuzurike Copyright © 2014 Susumu Inoue et al. All rights reserved. Molecularly Targeted Therapies in Multiple Myeloma Wed, 16 Apr 2014 12:34:52 +0000 http://www.hindawi.com/journals/lrt/2014/976567/ Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted. Pilar de la Puente, Barbara Muz, Feda Azab, Micah Luderer, and Abdel Kareem Azab Copyright © 2014 Pilar de la Puente et al. All rights reserved. Impact of Minimal Residual Disease, Detected by Flow Cytometry, on Outcome of Myeloablative Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia Sun, 23 Mar 2014 08:48:27 +0000 http://www.hindawi.com/journals/lrt/2014/421723/ In this retrospective study, we evaluated the impact of pre- and posttransplant minimal residual disease (MRD) detected by multiparametric flow cytometry (MFC) on outcome in 160 patients with ALL who underwent myeloablative allogeneic hematopoietic cell transplantation (HCT). MRD was defined as detection of abnormal B or T cells by MFC with no evidence of leukemia by morphology (<5% blasts in marrow) and no evidence of extramedullary disease. Among 153 patients who had pre-HCT flow data within 50 days before transplant, MRD pre-HCT increased the risk of relapse (hazard ratio (HR) = 3.64; 95% confidence interval (CI), 1.87–7.09; ) and mortality (HR = 2.39; 95% CI, 1.46–3.90, ). Three-year estimates of relapse were 17% and 38% and estimated 3-year OS was 68% and 40% for patients without and with MRD pre-HCT, respectively. 144 patients had at least one flow value post-HCT, and the risk of relapse among those with MRD was higher than that among those without MRD (HR = 7.47; 95% CI, 3.30–16.92, ). The risk of mortality was also increased (HR = 3.00; 95% CI, 1.44–6.28, ). These data suggest that pre- or post-HCT MRD, as detected by MFC, is associated with an increased risk of relapse and death after myeloablative HCT for ALL. Merav Bar, Brent L. Wood, Jerald P. Radich, Kristine C. Doney, Ann E. Woolfrey, Colleen Delaney, Frederick R. Appelbaum, and Ted A. Gooley Copyright © 2014 Merav Bar et al. All rights reserved. In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells Wed, 08 Jan 2014 09:17:16 +0000 http://www.hindawi.com/journals/lrt/2014/143479/ The combined use of the histone deacetylase inhibitor valproic acid (VPA), the retinoic acid receptor-α agonist all-trans retinoic acid (ATRA), and the deoxyribonucleic acid polymerase-α inhibitor cytarabine (Ara-C) is now considered for disease-stabilizing treatment of acute myeloid leukemia (AML). Leukemogenesis and leukemia cell chemoresistance seem to be supported by neighbouring stromal cells in the bone marrow, and we have therefore investigated the effects of these drugs on primary human endothelial cells and the osteoblastic Cal72 cell line. The results show that VPA and Ara-C have antiproliferative effects, and the antiproliferative/cytotoxic effect of Ara-C was seen at low concentrations corresponding to serum levels found during low-dose in vivo treatment. Furthermore, in functional assays of endothelial migration and tube formation VPA elicited an antiangiogenic effect, whereas ATRA elicited a proangiogenic effect. Finally, VPA and ATRA altered the endothelial cell release of angiogenic mediators; ATRA increased levels of CXCL8, PDGF-AA, and VEGF-D, while VPA decreased VEGF-D and PDGF-AA/BB levels and both drugs reduced MMP-2 levels. Several of these mediators can enhance AML cell proliferation and/or are involved in AML-induced bone marrow angiogenesis, and direct pharmacological effects on stromal cells may thus indirectly contribute to the overall antileukemic activity of this triple drug combination. Hilde Kvestad, Lasse Evensen, James B. Lorens, Øystein Bruserud, and Kimberley J. Hatfield Copyright © 2014 Hilde Kvestad et al. All rights reserved. Polymorphisms of MTHFR Associated with Higher Relapse/Death Ratio and Delayed Weekly MTX Administration in Pediatric Lymphoid Malignancies Tue, 10 Dec 2013 17:41:49 +0000 http://www.hindawi.com/journals/lrt/2013/238528/ Backgrounds. Outcome of childhood malignancy has been improved mostly due to the advances in diagnostic techniques and treatment strategies. While methotrexate (MTX) related polymorphisms have been under investigation in childhood malignancies, many controversial results have been offered. Objectives. To evaluate associations of polymorphisms related MTX metabolisms and clinical course in childhood lymphoid malignancies. Method. Eighty-two acute lymphoblastic leukemia and 21 non-Hodgkin’s lymphoma children were enrolled in this study. Four single nucleotide polymorphisms in 2 genes (MTHFR (rs1801133/c.677C>T/p.Ala222Val and rs1801131/c.1298A>C/p.Glu429Ala) and SLCO1B1 (rs4149056/c.521T>C/p.V174A and rs11045879/c.1865+4846T>C)) were genotyped by Taqman PCR method or direct sequencing. Clinical courses were reviewed retrospectively. Results. No patient who had the AC/CC genotype of rs1801131 (MTHFR) had relapsed or died, in which distribution was statistically different among the AA genotype of rs1801131 (). Polymorphisms of SLCO1B1 (rs11045879 and rs4149056) were not correlated with MTX concentrations, adverse events, or disease outcome. Conclusions. Polymorphisms of MTHFR (rs1801131) could be the plausive candidate for prognostic predictor in childhood lymphoid malignancies. Hiroko Fukushima, Takashi Fukushima, Aiko Sakai, Ryoko Suzuki, Ryoko Nakajima-Yamaguchi, Chie Kobayashi, Atsushi Iwabuchi, Makoto Saito, Ai Yoshimi, Tomohei Nakao, Keisuke Kato, Masahiro Tsuchida, Hideto Takahashi, Kazutoshi Koike, Nobutaka Kiyokawa, Emiko Noguchi, and Ryo Sumazaki Copyright © 2013 Hiroko Fukushima et al. All rights reserved. Rapid Infusion Rituximab for Maintenance Therapy: Is It Feasible? Thu, 31 Oct 2013 11:13:55 +0000 http://www.hindawi.com/journals/lrt/2013/629283/ Rituximab is an anti-CD-20 monoclonal antibody used in the management of lymphoproliferative disorders. The use of maintenance rituximab has improved progression free survival and overall survival in follicular lymphomas. Although rapid rituximab infusions have been studied extensively, there is little data on the use of rapid infusions during maintenance therapy for low grade lymphomas. The primary objective of this retrospective analysis was to evaluate the incidence of Grade 3 and 4 toxicities with maintenance rapid infusion rituximab according to the Common Terminology Criteria for Adverse Events version 4 (CTC v. 4). Secondary objectives included evaluating all grade infusion related adverse events and correlation of adverse events with varying schedules of rituximab maintenance therapy. All patients who received rapid infusion rituximab as maintenance therapy for low grade lymphoma between December 2007 and November 2011 were included. Rapid rituximab infusions were administered over 90 minutes. Demographic, laboratory and clinical data were collected. A total of 109 patients received 647 rapid rituximab infusions. Three patients experienced an adverse reaction which resulted in one grade 1 infusion reaction and three grade 3 infusion reactions. No patients required hospitalization. All 3 patients received pharmacological and/or supportive care to relieve symptoms associated with the reaction. Jolly Patel, Melissa Ho, Viet Ho, Celeste Bello, Benjamin Djulbegovic, Lubomir Sokol, and Gene Wetzstein Copyright © 2013 Jolly Patel et al. All rights reserved. Physical Activity in Adolescents following Treatment for Cancer: Influencing Factors Wed, 18 Sep 2013 13:51:28 +0000 http://www.hindawi.com/journals/lrt/2013/592395/ The purpose of this study was to examine physical activity levels and influencing individual and environmental factors in a group of adolescent survivors of cancer and a comparison group. Methods. The study was conducted using a “mixed methods” design. Quantitative data was collected from 48 adolescent survivors of cancer and 48 comparison adolescents using the Godin Leisure-Time Exercise Questionnaire, the Fatigue Scale—Adolescents, and the Amherst Health and Activity Study—Student Survey. Qualitative data was collected in individual semistructured interviews. Results. Reported leisure-time physical activity total scores were not significantly different between groups. Physical activity levels were positively correlated with adult social support factors in the group of adolescent survivors of cancer, but not in the comparison group. Time was the primary barrier to physical activity in both groups. Fatigue scores were higher for the comparison but were not associated with physical activity levels in either group. The qualitative data further supported these findings. Conclusions. Barriers to physical activity were common between adolescent survivors of cancer and a comparative group. Increased knowledge of the motivators and barriers to physical activity may help health care providers and families provide more effective health promotion strategies to adolescent survivors of pediatric cancer. Marilyn Wright, Angie Bryans, Kaylin Gray, Leah Skinner, and Amanda Verhoeve Copyright © 2013 Marilyn Wright et al. All rights reserved. The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias Tue, 09 Jul 2013 10:12:53 +0000 http://www.hindawi.com/journals/lrt/2013/275760/ The development of the genetic studies on acute myeloid leukemias (AMLs) has led to the identification of some recurrent genetic abnormalities. Their discovery was of fundamental importance not only for a better understanding of the molecular pathogenesis of AMLs, but also for the identification of new therapeutic targets. In this context, it is essential to identify AML-associated “driver” mutations, which have a causative role in leukemogenesis. Evidences accumulated during the last years indicate that activating internal tandem duplication mutations in FLT3 (FLT3-ITD), detected in about 20% of AMLs, represents driver mutations and valid therapeutic targets in AMLs. Furthermore, the screening of FLT3-ITD mutations has also considerably helped to improve the identification of more accurate prognostic criteria and of the therapeutic selection of patients. Ugo Testa and Elvira Pelosi Copyright © 2013 Ugo Testa and Elvira Pelosi. All rights reserved. Phase II Study of Bortezomib as a Single Agent in Patients with Previously Untreated or Relapsed/Refractory Acute Myeloid Leukemia Ineligible for Intensive Therapy Sun, 28 Apr 2013 17:39:24 +0000 http://www.hindawi.com/journals/lrt/2013/705714/ We explored the safety and efficacy of bortezomib given as single agent in patients with untreated or relapsed/refractory acute myeloid leukemia (AML), unfit for conventional chemotherapy. Fourteen patients were treated with bortezomib 1.5 mg/m2 administered twice weekly for two weeks, every 3 weeks. Median age was 70 years (range 60–81) and the median number of cycles delivered was 2 (range 1–4). Of 13 evaluable patients, in 8 (61%), the administration of bortezomib resulted in an antileukemic effect as demonstrated by peripheral blood and/or bone marrow blast reduction. In 4 (50%) of these 8, a decrease by 37% of transfusion requirement was also observed . Overall median survival was 4 months (range 0.25–10). Neurotoxicity was the most frequent adverse event with 7 of 13 (54%) patients experiencing grades 3-4 peripheral neuropathy. Neurotoxicity led to treatment discontinuation in 4 (57%) of 7. In conclusion, the observed anti-leukemic activity of bortezomib indicates that there is room for designing additional studies in which combination with other chemotherapeutic agents should be considered. Clinical registration no.: EUDRACT 2006-006923-38. Chiara Sarlo, Francesco Buccisano, Luca Maurillo, Mariagiovanna Cefalo, Luigi Di Caprio, Laura Cicconi, Concetta Ditto, Licia Ottaviani, Ambra Di Veroli, Maria Ilaria Del Principe, Maria Assunta Grasso, Daniela Nasso, Giovanna De Santis, Sergio Amadori, and Adriano Venditti Copyright © 2013 Chiara Sarlo et al. All rights reserved. New Quantitative Method to Identify NPM1 Mutations in Acute Myeloid Leukaemia Tue, 09 Apr 2013 11:28:19 +0000 http://www.hindawi.com/journals/lrt/2013/756703/ Somatic mutations in the NPM1 gene, which encodes for nucleophosmin, have been reported to be the most frequent genetic abnormalities found in acute myeloid leukaemia (AML). Their identification and quantification remain crucial for the patients’ residual disease monitoring. We investigated a new method that could represent a novel reliable alternative to sequencing for its identification. This method was based on high-resolution melting analysis in order to detect mutated patients and on an allele-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) for the identification and quantification of the transcripts carrying NPM1 mutations (NPM1m). Few patients carrying known NPM1m enabled us to set up a table with the different primers’ ΔCT values, identifying a profile for each mutation type. We then analysed a series of 337 AML patients' samples for NPM1 mutational status characterization and confirmed the ASO-RQ-PCR results by direct sequencing. We identified some mutations in 86 samples, and the results were fully correlated in 100% of the 36 sequenced samples. We also detected other rare NPM1m in two samples, that we confirmed by direct sequencing. This highly specific method provides a novel quick, useful, and costless tool, easy to use in routine practice. Sarah Huet, Laurent Jallades, Carole Charlot, Kaddour Chabane, Franck E. Nicolini, Mauricette Michallet, Jean-Pierre Magaud, and Sandrine Hayette Copyright © 2013 Sarah Huet et al. All rights reserved. Influence of Methylenetetrahydrofolate Reductase C677T, A1298C, and G80A Polymorphisms on the Survival of Pediatric Patients with Acute Lymphoblastic Leukemia Wed, 17 Oct 2012 13:45:19 +0000 http://www.hindawi.com/journals/lrt/2012/292043/ The influence of genic polymorphisms involved in metabolism of chemotherapeutic agents as the methotrexate (MTX) has been studied mainly in acute lymphoblastic leukemia (ALL) of childhood. Advances in treatment may be attributed to identification of prognostic factors added to chemotherapy protocol. The aim of this study was to analyze the association of the C677T, A1298C, and G80A polymorphisms on MTHFR gene and on the overall survival of pediatric patients with lymphoblastic leukemia treated with MTX according to the Brazilian protocol in 187 months. The C677T and G80A polymorphisms were genotyped by PCR-RFLP and A1298C polymorphism by allele-specific PCR. We observed that ALL patients presented rate (dead/alive) of 0.36 for the 677CC genotype, corresponding also to lower overall survival ; on the other hand, the 677TT genotype showed a better survival (98%). Thus, we believe that patients with 80AA genotype presented a small reduction in MTX plasma level, suggesting that ALL children, carrying the 80AA genotype, showed a high toxicity to MTX . Dayse Maria Vasconcelos de Deus, Elker Lene Santos de Lima, Rafaela Maria Seabra Silva, Edinalva Pereira Leite, and Maria Tereza Cartaxo Muniz Copyright © 2012 Dayse Maria Vasconcelos de Deus et al. All rights reserved. Influence of IL10 (G1082A) and TNFα (G308A) Polymorphisms on the Survival of Pediatric Patients with ALL Tue, 02 Oct 2012 11:53:10 +0000 http://www.hindawi.com/journals/lrt/2012/692348/ Interleukin 10 (IL10) is a pleiotropic cytokine that stimulates various hematopoietic cells. The tumor necrosis factor alpha (TNFα) is a cytokine that may influence the transcriptional activity induced by glucocorticoids. This study examined the impact of TNFα (G308A) and IL10 (G1082A) polymorphisms at promoter regions in relation to the overall survival of 105 children years) with acute lymphoblastic leukemia (ALL) for a period of 126 months, treated according to the protocol GBTLI99. The G1082A and G308A polymorphisms were identified by allele-specific PCR and PCR-RFLP, respectively. Patients with IL10AA genotype had a higher death ratio (44%, . Patients with both IL10AA and TNFAA genotypes showed the worst survival when compared with the IL10GG and TNFGA genotypes (. The results of this study revealed a lower survival among patients with IL10AA genotype and the concomitant occurrence of IL10AA and TNFAA genotypes. Dayse Maria Vasconcelos de Deus, Karina Araújo Lugo, and Maria Tereza Cartaxo Muniz Copyright © 2012 Dayse Maria Vasconcelos de Deus et al. All rights reserved. Differentiation and Cell Survival of Myeloid Leukemia Cells Tue, 31 Jul 2012 09:09:43 +0000 http://www.hindawi.com/journals/lrt/2012/370375/ George P. Studzinski, Geoffrey Brown, Michael Danilenko, Philip Hughes, and Ewa Marcinkowska Copyright © 2012 George P. Studzinski et al. All rights reserved. Clinical Experience Using Vitamin D and Analogs in the Treatment of Myelodysplasia and Acute Myeloid Leukemia: A Review of the Literature Mon, 30 Jul 2012 13:49:27 +0000 http://www.hindawi.com/journals/lrt/2012/125814/ Despite progress in understanding the biology of acute myeloid leukemia (AML), and despite advances in treatment, the majority of patients with AML die from the disease. The observation that Vitamin D can induce AML blast cells in vitro to differentiate along the monocytic lineage was made 30 years ago; however, it remains to translate this into a clinically meaningful strategy. This is a review of published clinical experience regarding the use of Vitamin D and its analogs, either alone or in combination with other agents, to treat AML. In many of these reports, investigators included patients with myelodysplasia (MDS) as well as AML patients in their treatment cohorts; therefore reports of Vitamin D and its analogs in treating MDS are included. This review documents heterogeneity in selection criteria for patients treated in these studies, the spectrum of Vitamin D analogs used in various studies, and the differing dosing strategies employed by investigators. Despite examples of occasional clinical efficacy, barriers remain to the successful application of Vitamin D in the treatment of MDS and AML. These include the lack of definition of a particularly sensitive target population, and the as yet unknown optimal choice of Vitamin D analog and dosing schedule. Jonathan S. Harrison and Alexander Bershadskiy Copyright © 2012 Jonathan S. Harrison and Alexander Bershadskiy. All rights reserved. PKCδ Regulates Translation Initiation through PKR and eIF2α in Response to Retinoic Acid in Acute Myeloid Leukemia Cells Sun, 15 Jul 2012 08:13:49 +0000 http://www.hindawi.com/journals/lrt/2012/482905/ Translation initiation and activity of eukaryotic initiation factor-alpha (eIF2α), the rate-limiting step of translation initiation, is often overactivated in malignant cells. Here, we investigated the regulation and role of eIF2α in acute promyelocytic (APL) and acute myeloid leukemia (AML) cells in response to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), the front-line therapies in APL. ATRA and ATO induce Ser-51 phosphorylation (inactivation) of eIF2α, through the induction of protein kinase C delta (PKCδ) and PKR, but not other eIF2α kinases, such as GCN2 and PERK in APL (NB4) and AML cells (HL60, U937, and THP-1). Inhibition of eIF2α reduced the expression of cellular proteins that are involved in apoptosis (DAP5/p97), cell cycle (p21Waf1/Cip1), differentiation (TG2) and induced those regulating proliferation (c-myc) and survival (p70S6K). PI3K/Akt/mTOR pathway is involved in regulation of eIF2α through PKCδ/PKR axis. PKCδ and p-eIF2α protein expression levels revealed a significant association between the reduced levels of PKCδ (𝑃=0.0378) and peIF2 (𝑃=0.0041) and relapses in AML patients (𝑛=47). In conclusion, our study provides the first evidence that PKCδ regulates/inhibits eIF2α through induction of PKR in AML cells and reveals a novel signaling mechanism regulating translation initiation. Bulent Ozpolat, Ugur Akar, Ibrahim Tekedereli, S. Neslihan Alpay, Magaly Barria, Baki Gezgen, Nianxiang Zhang, Kevin Coombes, Steve Kornblau, and Gabriel Lopez-Berestein Copyright © 2012 Bulent Ozpolat et al. All rights reserved. MicroRNAs in Acute Myeloid Leukemia and Other Blood Disorders Sun, 17 Jun 2012 18:34:43 +0000 http://www.hindawi.com/journals/lrt/2012/603830/ Common blood disorders include hematopoietic cell malignancies or leukemias and plasma cell dyscrasia, all of which have associated microRNA abnormalities. In this paper, we discuss several leukemias including acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) and identify altered microRNAs and their targets. Immune disorders with altered blood levels of antibodies include autoimmune disorders, such as systemic lupus erythematosus (SLE) with associated anti-self-autoantibodies and immunoglobulin A nephropathy (IgAN) also have related microRNA abnormalities. The alterations in microRNAs may serve as therapeutic targets in these blood disorders. Yao Yuan, Siddha Kasar, Chingiz Underbayev, Sindhuri Prakash, and Elizabeth Raveche Copyright © 2012 Yao Yuan et al. All rights reserved. Retinoid Differentiation Therapy for Common Types of Acute Myeloid Leukemia Tue, 12 Jun 2012 08:21:51 +0000 http://www.hindawi.com/journals/lrt/2012/939021/ Many cancers arise in a tissue stem cell, and cell differentiation is impaired resulting in an accumulation of immature cells. The introduction of all-trans retinoic acid (ATRA) in 1987 to treat acute promyelocytic leukemia (APL), a rare subtype of acute myeloid leukemia (AML), pioneered a new approach to obtain remission in malignancies by restoring the terminal maturation of leukemia cells resulting in these cells having a limited lifespan. Differentiation therapy also offers the prospect of a less aggressive treatment by virtue of attenuated growth of leukemia cells coupled to limited damage to normal cells. The success of ATRA in differentiation therapy of APL is well known. However, ATRA does not work in non-APL AML. Here we examine some of the molecular pathways towards new retinoid-based differentiation therapy of non-APL AML. Prospects include modulation of the epigenetic status of ATRA-insensitive AML cells, agents that influence intracellular signalling events that are provoked by ATRA, and the use of novel synthetic retinoids. Geoffrey Brown and Philip Hughes Copyright © 2012 Geoffrey Brown and Philip Hughes. All rights reserved. Cell-Type-Specific Effects of Silibinin on Vitamin D-Induced Differentiation of Acute Myeloid Leukemia Cells Are Associated with Differential Modulation of RXRα Levels Sun, 20 May 2012 09:16:45 +0000 http://www.hindawi.com/journals/lrt/2012/401784/ Plant polyphenols have been shown to enhance the differentiation of acute myeloid leukemia (AML) cells induced by the hormonal form of vitamin D3 (1α,25-dihydroxyvitamin D3; 1,25D). However, how these agents modulate 1,25D effects in different subtypes of AML cells remains poorly understood. Here, we show that both carnosic acid (CA) and silibinin (SIL) synergistically enhancd 1,25D-induced differentiation of myeloblastic HL60 cells. However, in promonocytic U937 cells, only CA caused potentiation while SIL attenuated 1,25D effect. The enhanced effect of 1,25D+CA was accompanied by increases in both the vitamin D receptor (VDR) and retinoid X receptor alpha (RXRα) protein levels and vitamin D response element (VDRE) transactivation in both cell lines. Similar increases were observed in HL60 cells treated with 1,25D + SIL. In U937 cells, however, SIL inhibited 1,25D-induced VDRE transactivation concomitant with downregulation of RXRα at both transcriptional and posttranscriptional levels. These inhibitory effects correlated with the inability of SIL, with or without 1,25D, to activate the Nrf2/antioxidant response element signaling pathway in U937 cells. These results suggest that opposite effects of SIL on 1,25D-induced differentiation of HL60 and U937 cells may be determined by cell-type-specific signaling and transcriptional responses to this polyphenol resulting in differential modulation of RXRα expression. Rina Wassermann, Victoria Novik, and Michael Danilenko Copyright © 2012 Rina Wassermann et al. All rights reserved. Regulation of Leukemic Cell Differentiation through the Vitamin D Receptor at the Levels of Intracellular Signal Transduction, Gene Transcription, and Protein Trafficking and Stability Mon, 14 May 2012 09:18:03 +0000 http://www.hindawi.com/journals/lrt/2012/713243/ 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D) exerts its biological activities through vitamin D receptor (VDR), which is a member of the superfamily of steroid receptors, that act as ligand-dependent transcription factors. Ligated VDR in complex with retinoid X receptor (RXR) binds to regulatory regions of 1,25(OH)2D-target genes. 1,25(OH)2D is able to induce differentiation of leukemic blasts towards macrophage-like cells. Many different acute myeloid leukemia (AML) cell lines respond to 1,25(OH)2D by increasing CD14 cell surface receptor, some additionally upregulate CD11b and CD11c integrins. In untreated AML cells VDR protein is present in cytosol at a very low level, even though its mRNA is continuously expressed. Ligation of VDR causes protein stabilization and translocation to the cell nuclei, where it regulates transcription of target genes. Several important groups of genes are regulated by 1,25(OH)2D in HL60 cells. These genes include differentiation-related genes involved in macrophage function, as well as a gene regulating degradation of 1,25(OH)2D, namely CYP24A1. We summarize here the data which demonstrate that though some cellular responses to 1,25(OH)2D in AML cells are transcription-dependent, there are many others which depend on intracellular signal transduction, protein trafficking and stabilization. The final effect of 1,25(OH)2D action in leukemic cells requires all these acting together. Elżbieta Gocek, Hanna Baurska, Aleksandra Marchwicka, and Ewa Marcinkowska Copyright © 2012 Elżbieta Gocek et al. All rights reserved. HTLV-1 Infection and Its Associated Diseases Mon, 07 May 2012 09:13:47 +0000 http://www.hindawi.com/journals/lrt/2012/123637/ Mineki Saito, Pooja Jain, Kunihiro Tsukasaki, and Charles R. M. Bangham Copyright © 2012 Mineki Saito et al. All rights reserved. The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia Tue, 24 Apr 2012 11:01:34 +0000 http://www.hindawi.com/journals/lrt/2012/671702/ Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML. Gabriela Nestal de Moraes, Paloma Silva Souza, Fernanda Casal de Faria Costas, Flavia Cunha Vasconcelos, Flaviana Ruade Souza Reis, and Raquel Ciuvalschi Maia Copyright © 2012 Gabriela Nestal de Moraes et al. All rights reserved. Mycophenolic Acid Overcomes Imatinib and Nilotinib Resistance of Chronic Myeloid Leukemia Cells by Apoptosis or a Senescent-Like Cell Cycle Arrest Thu, 23 Feb 2012 12:54:17 +0000 http://www.hindawi.com/journals/lrt/2012/861301/ We used K562 cells sensitive or generated resistant to imatinib or nilotinib to investigate their response to mycophenolic acid (MPA). MPA induced DNA damage leading to cell death with a minor contribution of apoptosis, as revealed by annexin V labeling (up to 25%). In contrast, cell cycle arrest and positive staining for senescence-associated β-galactosidase activity were detected for a large cell population (80%). MPA-induced cell death was potentialized by the inhibition of autophagy and this is associated to the upregulation of apoptosis. In contrast, senescence was neither decreased nor abrogated in autophagy deficient K562 cells. Primary CD34 cells from CML patients sensitive or resistant to imatinib or nilotinib respond to MPA although apoptosis is mainly detected. These results show that MPA is an interesting tool to overcome resistance in vitro and in vivo mainly in the evolved phase of the disease. Claire Drullion, Valérie Lagarde, Romain Gioia, Patrick Legembre, Muriel Priault, Bruno Cardinaud, Eric Lippert, François-Xavier Mahon, and Jean-Max Pasquet Copyright © 2012 Claire Drullion et al. All rights reserved. Factor V Leiden and Prothrombin 20210A Mutations among Turkish Pediatric Leukemia Patients Thu, 16 Feb 2012 10:54:20 +0000 http://www.hindawi.com/journals/lrt/2012/250432/ This study was undertaken to determine the prevalence of the Factor V 1691 G-A and PT 20210 G-A mutations in Turkish children with leukemia. We genotyped 135 pediatric leukemia patients with for these mutations. Eleven (8%) of the 135 patients were heterozygous for the FV 1691 G-A mutation. Seven (5,1%) of the patients carried the PT 20210 G-A heterozygous mutation. Of the 135 patients, only three had thrombotic event, none of which had these two mutations, which is common in Turkish population. Our findings revealed a controversial compared to the previous reports, which needs further investigation. Dilara Fatma Akın, Kadir Sipahi, Tuğba Kayaalp, Yonca Eğin, Serpil Taşdelen, Emin Kürekçi, Üstün Ezer, and Nejat Akar Copyright © 2012 Dilara Fatma Akın et al. All rights reserved. Identification of a Novel P190-Derived Breakpoint Peptide Suitable for Peptide Vaccine Therapeutic Approach in Ph+ Acute Lymphoblastic Leukemia Patients Wed, 15 Feb 2012 11:51:05 +0000 http://www.hindawi.com/journals/lrt/2012/150651/ Ph+ acute lymphoblastic leukemia (Ph+ ALL) is a high-risk acute leukemia with poor prognosis, in which the specific t(9;22)(q34;q11) translocation results in a chimeric bcr-abl (e1a2 breakpoint) and in a 190 KD protein (p190) with constitutive tyrosine kinase activity. The advent of first- and second-generation tyrosine kinase inhibitors (TKIs) improved the short-term outcome of Ph+ ALL patients not eligible for allo-SCT; yet disease recurrence is almost inevitable. Peptides derived from p190-breakpoint area are leukemia-specific antigens that may mediate an antitumor response toward p190+ leukemia cells. We identified one peptide named p190-13 able to induce in vitro peptide-specific CD4+ T cell proliferation in Ph+ ALL patients in complete remission during TKIs. Thus this peptide appears a good candidate for developing an immune target vaccine strategy possibly synergizing with TKIs for remission maintenance. Micaela Ippoliti, Marzia Defina, Antonella Gozzini, Claudia Baratè, Lara Aprile, Alice Pietrini, Alessandro Gozzetti, Donatella Raspadori, Francesco Lauria, and Monica Bocchia Copyright © 2012 Micaela Ippoliti et al. All rights reserved. Clinical Trials of Adult T-Cell Leukaemia/Lymphoma Treatment Tue, 14 Feb 2012 13:15:27 +0000 http://www.hindawi.com/journals/lrt/2012/932175/ Adult T-cell leukaemia/lymphoma (ATLL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I (HTLV-1). Prognosis is severe because of intrinsic chemoresistance and severe immuosuppression. Four different subtypes are described with different outcomes, and treatment strategies vary according to the different clinical courses. Japanese trials show that combinations of chemotherapy can increase the response rates especially in the lymphoma subtype. However, patients have a high rate of relapse and the outcome remains extremely poor. Recently, a worldwide meta-analysis demonstrated that the combination of Zidovudine and Interferon-alpha (IFN) is effective in the leukemic subtypes (smoldering, chronic, and acute) and influences favorably the course of the disease. In order to prevent relapse, clinical trials testing new drugs such as monoclonal antibodies or combinations such as arsenic/IFN are needed. Finally, allogeneic stem cell transplantation is a feasible option but bears a very high rate of complications. Ambroise Marçais, Felipe Suarez, David Sibon, Ali Bazarbachi, and Olivier Hermine Copyright © 2012 Ambroise Marçais et al. All rights reserved. Important Genes in the Pathogenesis of 5q- Syndrome and Their Connection with Ribosomal Stress and the Innate Immune System Pathway Mon, 13 Feb 2012 10:16:56 +0000 http://www.hindawi.com/journals/lrt/2012/179402/ Myelodysplastic syndrome (MDS) with interstitial deletion of a segment of the long arm of chromosome 5q [del(5q)] is characterized by bone marrow erythroid hyperplasia, atypical megakaryocytes, thrombocythemia, refractory anemia, and low risk of progression to acute myeloid leukemia (AML) compared with other types of MDS. The long arm of chromosome 5 contains two distinct commonly deleted regions (CDRs). The more distal CDR lies in 5q33.1 and contains 40 protein-coding genes and genes coding microRNAs (miR-143, miR-145). In 5q-syndrome one allele is deleted that accounts for haploinsufficiency of these genes. The mechanism of erythroid failure appears to involve the decreased expression of the ribosomal protein S14 (RPS14) gene and the upregulation of the p53 pathway by ribosomal stress. Friend leukemia virus integration 1 (Fli1) is one of the target genes of miR145. Increased Fli1 expression enables effective megakaryopoiesis in 5q-syndrome. Ota Fuchs Copyright © 2012 Ota Fuchs. All rights reserved. Cotranscriptional Chromatin Remodeling by Small RNA Species: An HTLV-1 Perspective Thu, 09 Feb 2012 09:39:29 +0000 http://www.hindawi.com/journals/lrt/2012/984754/ Cell type specificity of human T cell leukemia virus 1 has been proposed as a possible reason for differential viral outcome in primary target cells versus secondary. Through chromatin remodeling, the HTLV-1 transactivator protein Tax interacts with cellular factors at the chromosomally integrated viral promoter to activate downstream genes and control viral transcription. RNA interference is the host innate defense mechanism mediated by short RNA species (siRNA or miRNA) that regulate gene expression. There exists a close collaborative functioning of cellular transcription factors with miRNA in order to regulate the expression of a number of eukaryotic genes including those involved in suppression of cell growth, induction of apoptosis, as well as repressing viral replication and propagation. In addition, it has been suggested that retroviral latency is influenced by chromatin alterations brought about by miRNA. Since Tax requires the assembly of transcriptional cofactors to carry out viral gene expression, there might be a close association between miRNA influencing chromatin alterations and Tax-mediated LTR activation. Herein we explore the possible interplay between HTLV-1 infection and miRNA pathways resulting in chromatin reorganization as one of the mechanisms determining HTLV-1 cell specificity and viral fate in different cell types. Nishat Aliya, Saifur Rahman, Zafar K. Khan, and Pooja Jain Copyright © 2012 Nishat Aliya et al. All rights reserved. Immunopathogenesis of Human T-Cell Leukemia Virus Type-1-Associated Myelopathy/Tropical Spastic Paraparesis: Recent Perspectives Mon, 06 Feb 2012 15:41:00 +0000 http://www.hindawi.com/journals/lrt/2012/259045/ Human T-cell leukemia virus type-1 (HTLV-1) is a replication-competent human retrovirus associated with two distinct types of disease only in a minority of infected individuals: the malignancy known as adult T-cell leukemia (ATL) and a chronic inflammatory central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic progressive myelopathy characterized by spastic paraparesis, sphincter dysfunction, and mild sensory disturbance in the lower extremities. Although the factors that cause these different manifestations of HTLV-1 infection are not fully understood, accumulating evidence from host population genetics, viral genetics, DNA expression microarrays, and assays of lymphocyte function suggests that complex virus-host interactions and the host immune response play an important role in the pathogenesis of HAM/TSP. Especially, the efficiency of an individual's cytotoxic T-cell (CTL) response to HTLV-1 limits the HTLV-1 proviral load and the risk of HAM/TSP. This paper focuses on the recent advances in HAM/TSP research with the aim to identify the precise mechanisms of disease, in order to develop effective treatment and prevention. Mineki Saito and Charles R. M. Bangham Copyright © 2012 Mineki Saito and Charles R. M. Bangham. All rights reserved. Clinical Trials and Treatment of ATL Mon, 16 Jan 2012 15:15:29 +0000 http://www.hindawi.com/journals/lrt/2012/101754/ ATL is a distinct peripheral T-lymphocytic malignancy associated with human T-cell lymphotropic virus type I (HTLV-1). The diversity in clinical features and prognosis of patients with this disease has led to its subtype-classification into four categories, acute, lymphoma, chronic, and smoldering types, defined by organ involvement, and LDH and calcium values. In case of acute, lymphoma, or unfavorable chronic subtypes (aggressive ATL), intensive chemotherapy like the LSG15 regimen (VCAP-AMP-VECP) is usually recommended if outside of clinical trials, based on the results of a phase 3 trial. In case of favorable chronic or smoldering ATL (indolent ATL), watchful waiting until disease progression has been recommended, although the long-term prognosis was inferior to those of, for instance, chronic lymphoid leukemia. Retrospective analysis suggested that the combination of interferon alpha and zidovudine was apparently promising for the treatment of ATL, especially for types with leukemic manifestation. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is also promising for the treatment of aggressive ATL possibly reflecting graft versus ATL effect. Several new agent trials for ATL are ongoing and in preparation, including a defucosylated humanized anti-CC chemokine receptor 4 monoclonal antibody, IL2-fused with diphtheria toxin, histone deacetylase inhibitors, a purine nucleoside phosphorylase inhibitor, a proteasome inhibitor, and lenalidomide. Kunihiro Tsukasaki and Kensei Tobinai Copyright © 2012 Kunihiro Tsukasaki and Kensei Tobinai. All rights reserved.