Functional characterization of a novel FGFR1OP-RET rearrangement in hematopoietic malignancies.

Posted by rob on October 16, 2014 under Uncategorized | Comments are off for this article

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Functional characterization of a novel FGFR1OP-RET rearrangement in hematopoietic malignancies.

Mol Oncol. 2014 Mar;8(2):221-31

Authors: Bossi D, Carlomagno F, Pallavicini I, Pruneri G, Trubia M, Raviele PR, Marinelli A, Anaganti S, Cox MC, Viale G, Santoro M, Di Fiore PP, Minucci S

Abstract

The RET (REarranged during Transfection) receptor tyrosine kinase is targeted by oncogenic rearrangements in thyroid and lung adenocarcinoma. Recently, a RET (exon 12) rearrangement with FGFR1OP [fibroblast growth factor receptor 1 (FGFR1) oncogene partner] (exon 12) was identified in one chronic myelomonocytic leukemia (CMML) patient. We report the molecular cloning and functional characterization of a novel FGFR1OP (exon 11)-RET (exon 11) gene fusion event (named FGFR1OP-RET), mediated by a reciprocal translocation t(6; 10)(q27; q11), in a patient affected by primary myelofibrosis (PMF) with secondary acute myeloid leukemia (AML). The FGFR1OP-RET fusion protein displayed constitutive tyrosine kinase and transforming activity in NIH3T3 fibroblasts, and induced IL3-independent growth and activation of PI3K/STAT signaling in hematopoietic Ba/F3 cells. FGFR1OP-RET supported cytokine-independent growth, protection from stress and enhanced self-renewal of primary murine hematopoietic progenitor and stem cells in vitro. In vivo, FGFR1OP-RET caused a spectrum of disease phenotypes, with >50% of mice showing a fatal myeloproliferative disorder (MPD). Other phenotypes were leukemia transplantable in secondary recipients, dramatic expansion of the mast cell lineage, and reduction of repopulating activity upon lethal irradiation. In conclusion, FGFR1OP-RET chimeric oncogenes are endowed with leukemogenic potential and associated to myeloid neoplasms (CMML and PMF/AML).

PMID: 24315414 [PubMed - indexed for MEDLINE]

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Ever-advancing chronic myeloid leukemia treatment.

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Ever-advancing chronic myeloid leukemia treatment.

Int J Clin Oncol. 2014 Feb;19(1):3-9

Authors: Kimura S, Ando T, Kojima K

Abstract

Treatment of chronic myeloid leukemia (CML) has been drastically changed by the emergence of the ABL tyrosine kinase inhibitor (TKI), imatinib mesylate. However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the ABL kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. To overcome this resistance, four second-generation ATP competitive ABL TKIs, dasatinib, nilotinib, bosutinib and bafetinib, have been developed. Dasatinib and nilotinib also demonstrated higher efficacy than imatinib in previously untreated CML patients in chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a third-generation ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harbouring T315I. CML treatment is rapidly progressing and further evolution is surely expected. Moreover, it was recently reported that some CML patients who achieved sustained complete molecular response could stop TKI. CML may become the first human cancer to be conquered solely with oral medicines.

PMID: 24258348 [PubMed - indexed for MEDLINE]

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Recent improvement in completeness of incidence data on acute myeloid leukemia in US cancer registries.

Posted by rob on October 15, 2014 under Uncategorized | Comments are off for this article

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Recent improvement in completeness of incidence data on acute myeloid leukemia in US cancer registries.

J Registry Manag. 2014;41(2):77-84

Authors: Polednak AP

Abstract

A limitation of data prior to 2010 on incidence of leukemia in US population-based cancer registries is that acute myeloid leukemia (AML) diagnosed as progression (transformation) from a previously diagnosed myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN, other than polycythemia vera), or chronic myeloid leukemia (CML) was not reportable. Data were used from a research database for the 18 cancer registries of the Surveillance, Epidemiology and End Results (SEER) Program, and from all registries in the US Cancer Statistics (USCS) database. Analyses compared the age-standardized incidence rate (ASIR) per 100,000 for AML before (ie, 2000-2009) vs after (ie, 2010) the new reportability rules for AML. The ASIR for all ages combined fluctuated until increasing from 3.60 (95 percent CI, 3.47-3.73; N = 3,068) in 2009 to 3.89 (95 percent CI, 3.76-4.03; N = 3,355) in 2010 in SEER, and from 3.64 (95 percent CI, 3.58-3.71; N = 11,488) in 2009 to 3.89 (95 percent CI, 3.82-3.96; N = 12,351) in 2010 in USCS. The increase from 2009 to 2010 was limited to ages 60+ years (from 13.87 to 15.59 in SEER and from 14.13 to 15.34 in USCS). The SEER research database allowed analysis by the number of cancers per person, which showed that the increase in AML cases and rates for age 60+ years from 2009 to 2010 was due to an increase in cases with a previous cancer(s) largely representing newly-reportable post-MDS, post-MPN and post-CML AML cases. Continued surveillance is needed to address the eventual impact of delayed reporting of diagnoses in 2010 on estimates and projections of AML incidence in the US population.

PMID: 25153013 [PubMed - indexed for MEDLINE]

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Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1).

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Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1).

Clin Cancer Res. 2014 Feb 15;20(4):985-94

Authors: Nies AT, Schaeffeler E, van der Kuip H, Cascorbi I, Bruhn O, Kneba M, Pott C, Hofmann U, Volk C, Hu S, Baker SD, Sparreboom A, Ruth P, Koepsell H, Schwab M

Abstract

PURPOSE: In addition to mutated BCR-ABL1 kinase, the organic cation transporter 1 (OCT1, encoded by SLC22A1) has been considered to contribute to imatinib resistance in patients with chronic myeloid leukemia (CML). As data are conflicting as to whether OCT1 transports imatinib and may serve as a clinical biomarker, we used a combination of different approaches including animal experiments to elucidate comprehensively the impact of OCT1 on cellular imatinib uptake.

EXPERIMENTAL DESIGN: Transport of imatinib was studied using OCT1-expressing Xenopus oocytes, mammalian cell lines (HEK293, MDCK, V79) stably expressing OCT1, human leukemic cells, and Oct1-knockout mice. OCT1 mRNA and protein expression were analyzed in leukemic cells from patients with imatinib-naïve CML as well as in cell lines.

RESULTS: Transport and inhibition studies showed that overexpression of functional OCT1 protein in Xenopus oocytes or mammalian cell lines did not lead to an increased cellular accumulation of imatinib. The CML cell lines (K562, Meg-01, LAMA84) and leukemic cells from patients expressed neither OCT1 mRNA nor protein as demonstrated by immunoblotting and immunofluorescence microscopy, yet they showed a considerable imatinib uptake. Oct1 deficiency in mice had no influence on plasma and hepatic imatinib concentrations.

CONCLUSIONS: These data clearly demonstrate that cellular uptake of imatinib is independent of OCT1, and therefore OCT1 is apparently not a valid biomarker for imatinib resistance.

PMID: 24352644 [PubMed - indexed for MEDLINE]

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Comparison of continuous and twice-daily infusions of cyclosporine A for graft-versus-host-disease prophylaxis in pediatric hematopoietic stem cell transplantation.

Posted by rob on October 14, 2014 under Uncategorized | Comments are off for this article

Comparison of continuous and twice-daily infusions of cyclosporine A for graft-versus-host-disease prophylaxis in pediatric hematopoietic stem cell transplantation.

Pediatr Blood Cancer. 2014 Oct 12;

Authors: Umeda K, Adachi S, Tanaka S, Ogawa A, Hatakeyama N, Kudo K, Sakata N, Igarashi S, Ohshima K, Hyakuna N, Chin M, Goto H, Takahashi Y, Azuma E, Koh K, Sawada A, Kato K, Inoue M, Atsuta Y, Takami A, Murata M, on behalf of the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation

Abstract

BACKGROUND: Cyclosporine A (CsA) is used widely for graft-versus-host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation (HSCT); however, the optimal schedule of its administration has not been established. Although comparative studies of adult patients undergoing HSCT have demonstrated enhanced efficacy and safety of twice-daily infusion (TD) compared with continuous infusion (CIF) of CsA, to our knowledge, similar studies have not yet been performed in pediatric groups.

PROCEDURE: A self-administered questionnaire was used to retrospectively compare the clinical outcome and incidence of CsA-associated adverse events of 70 pediatric acute myelogenous leukemia patients who were receiving CsA by TD (n?=?36) or CIF (n?=?34) as GVHD prophylaxis for their first allogeneic HSCT.

RESULTS: The cumulative incidences of grade II-IV acute GVHD and chronic GVHD, as well as the overall survival and event-free survival rates, did not differ significantly between the TD and CIF groups; however, the incidence of severe hypertension was significantly higher in the CIF group than the TD group.

CONCLUSIONS: The analysis presented here indicates that TD and CIF administration of CsA have similar prophylactic effect on pediatric GVHD and suggest that TD is associated with a lower rate of toxicity than CIF in pediatric patients undergoing HSCT. Pediatr Blood Cancer 2014;9999:1-8. © 2014 Wiley Periodicals, Inc.

PMID: 25307105 [PubMed - as supplied by publisher]

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Regulation of the interferon regulatory factor-8 (IRF-8) tumor suppressor gene by the signal transducer and activator of transcription 5 (STAT5) transcription factor in chronic myeloid leukemia.

Posted by rob on October 11, 2014 under Uncategorized | Comments are off for this article

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Regulation of the interferon regulatory factor-8 (IRF-8) tumor suppressor gene by the signal transducer and activator of transcription 5 (STAT5) transcription factor in chronic myeloid leukemia.

J Biol Chem. 2014 May 30;289(22):15642-52

Authors: Waight JD, Banik D, Griffiths EA, Nemeth MJ, Abrams SI

Abstract

Tyrosine kinase inhibitors such as imatinib can effectively target the BCR-ABL oncoprotein in a majority of patients with chronic myeloid leukemia (CML). Unfortunately, some patients are resistant primarily to imatinib and others develop drug resistance, prompting interest in the discovery of new drug targets. Although much of this resistance can be explained by the presence of mutations within the tyrosine kinase domain of BCR-ABL, such mutations are not universally identified. Interferon regulatory factor-8 (IRF-8) is a transcription factor that is essential for myelopoiesis. Depressed IRF-8 levels are observed in a majority of CML patients and Irf-8(-/-) mice exhibit a CML-like disease. The underlying mechanisms of IRF-8 loss in CML are unknown. We hypothesized that BCR-ABL suppresses transcription of IRF-8 through STAT5, a proximal BCR-ABL target. Treatment of primary cells from newly diagnosed CML patients in chronic phase as well as BCR-ABL(+) cell lines with imatinib increased IRF-8 transcription. Furthermore, IRF-8 expression in cell line models was necessary for imatinib-induced antitumor responses. We have demonstrated that IRF-8 is a direct target of STAT5 and that silencing of STAT5 induced IRF-8 expression. Conversely, activating STAT5 suppressed IRF-8 transcription. Finally, we showed that STAT5 blockade using a recently discovered antagonist increased IRF-8 expression in patient samples. These data reveal a previously unrecognized BCR-ABL-STAT5-IRF-8 network, which widens the repertoire of potentially new anti-CML targets.

PMID: 24753251 [PubMed - indexed for MEDLINE]

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Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

Posted by rob on October 10, 2014 under Uncategorized | Comments are off for this article

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Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

Cancer Chemother Pharmacol. 2014 Oct 9;

Authors: Gotta V, Widmer N, Decosterd LA, Chalandon Y, Heim D, Gregor M, Benz R, Leoncini-Franscini L, Baerlocher GM, Duchosal MA, Csajka C, Buclin T

Abstract

PURPOSE: This study assessed whether a cycle of “routine” therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems (“rescue” TDM).

METHODS: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to “routine TDM” or “rescue TDM.” The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395).

RESULTS: Among 56 patients (55 evaluable), 14/27 (52 %) receiving “routine TDM” remained event-free versus 16/28 (57 %) “rescue TDM” controls (P = 0.69). In the “routine TDM” arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml).

CONCLUSIONS: This first target concentration intervention trial could not formally demonstrate a benefit of “routine TDM” because of small patient number and surprisingly limited prescriber’s adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

PMID: 25297989 [PubMed - as supplied by publisher]

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Methylation status of CEBPA gene promoter in chronic myeloid leukemia.

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Methylation status of CEBPA gene promoter in chronic myeloid leukemia.

Hematology. 2014 Jan;19(1):42-4

Authors: Annamaneni S, Kagita S, Gorre M, Digumarti RR, Satti V, Battini MR

Abstract

CCAAT/enhancer binding protein alpha is one of the crucial transcription factors for myeloid cell development that has been found to be involved in hematopoietic differentiation and leukemiogenesis. Recently, epigenetic regulation of CEBPA expression through DNA methylation has been demonstrated in leukemia. The aim of this study was to investigate the methylation status of CEBPA gene in chronic myeloid leukemia (CML) patients. The methylation status of CEBPA promoter was studied in 100 patients with CML and 98 normal healthy individuals from Hyderabad, India, using methylation-specific polymerase chain reaction. The aberrant methylation of CEBPA gene promoter was found in 32 of the 100 CML cases. A highly significant association was found between the frequency of CEBPA gene promoter hypermethylation and the CML stages (P = 0.017), but association with respect to age and gender of the patient was not found. The results suggest that aberrant methylation in the CpG island of the promoter region of this gene might be a common event in CML, and systemic expression studies will be needed to unfold the role of CEBPA promoter methylation in the development, progression, and prognosis of CML.

PMID: 23541085 [PubMed - indexed for MEDLINE]

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National trends in spending on and use of oral oncologics, first quarter 2006 through third quarter 2011.

Posted by rob on October 8, 2014 under Uncategorized | Comments are off for this article

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National trends in spending on and use of oral oncologics, first quarter 2006 through third quarter 2011.

Health Aff (Millwood). 2014 Oct 1;33(10):1721-7

Authors: Conti RM, Fein AJ, Bhatta SS

Abstract

Oral prescription drugs are an increasingly important treatment option for cancer. Yet contemporaneous US trends in spending on anticancer drugs known as oral oncologics have not been described. Using nationally representative data, we describe trends in national spending on and use of forty-seven oral oncologics between the first quarter of 2006 and the third quarter of 2011. Average quarterly national spending on oral oncologics increased 37 percent, from $940.3 million to $1.4 billion in 2012 dollars, a significant change. Average quarterly use of oral oncologics in the same time period measured in extended units increased at a significant pace but more slowly than spending (10 percent). Within this broader trend, differences in spending among categories of oral oncologics were observed. High levels of and increases in both spending and use were concentrated among new brand-name and patent-protected oral oncologics, including second-generation tyrosine kinase inhibitors used to treat chronic myelogenous leukemia. Decreased spending but increased use was observed among oral oncologics that lost patent protection during the study period and were available in generic form, including hormonal therapies used to treat breast and prostate cancers. Spending on new and patent-protected oral oncologics and associated price increases are significant drivers of increased spending.

PMID: 25288415 [PubMed - in process]

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Targeting the MYC and PI3K pathways eliminates leukemia-initiating cells in T cell acute lymphoblastic leukemia.

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Targeting the MYC and PI3K pathways eliminates leukemia-initiating cells in T cell acute lymphoblastic leukemia.

Cancer Res. 2014 Oct 6;

Authors: Schubbert S, Cardenas A, Chen H, Garcia C, Guo W, Bradner JE, Wu H

Abstract

Disease relapse remains the major clinical challenge in treating T cell acute lymphoblastic leukemia (T-ALL), particularly those with PTEN loss. We hypothesized that leukemia-initiating cells (LICs) are responsible for T-ALL development and treatment relapse. In this study, we used a genetically engineered mouse model of Pten(-/-) T-ALL with defined blast and LIC-enriched cell populations to demonstrate that LICs are responsible for therapeutic resistance. Unlike acute and chronic myelogenous leukemia, LICs in T-ALL were actively cycling, were distinct biologically and responded differently to targeted therapies in comparison to their differentiated blast cell progeny. Notably, we found that T-ALL LICs could be eliminated by co-targeting the deregulated pathways driven by phosphoinositide 3-kinase (PI3K) and Myc, which are altered commonly in human T-ALL and are associated with LIC formation. Our findings define critical events that may be targeted to eliminate LICs in T-ALL as a new strategy to treat the most aggressive relapsed forms of this disease.

PMID: 25287161 [PubMed - as supplied by publisher]

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[Advances in the target therapy of hematological malignancies].

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[Advances in the target therapy of hematological malignancies].

Sichuan Da Xue Xue Bao Yi Xue Ban. 2014 Jul;45(4):642-6

Authors: Niu T, Liu T

Abstract

With the rapid development of modern bio-medical technology, the pathogenesis of hematological malignancies including leukemia, lymphoma, myeloma has been illustrated with more and more attractive details. The diagnosis of hematological malignancies now becomes more precisely and clarified based on the progress than ever before, and the treatments of hematological malignancies keep the evolution in the way of integrating the novel molecular target drugs with conventional chemotherapy, radiotherapy, hematopoietic stem cell transplantation. The pivotal progress in the target therapy of hematological malignancies includes tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia, CD20 monoclonal antibody treatment of B-cell lymphoma and CD20 positive leukemia, FLT3 inhibitors fo the treatment of FLT3 mutation positive high-risk acute myelogenous leukemia. The topics of this issue focus on the advances in this field, which reflects the new achievements in the research of hematological malignancies, and the trends of precise and stratified diagnosis as well as tailored target therapy in the future.

PMID: 25286692 [PubMed - in process]

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High frequency of BTG1 deletions in patients with BCR-ABL1-positive acute leukemia.

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High frequency of BTG1 deletions in patients with BCR-ABL1-positive acute leukemia.

Cancer Genet. 2014 May;207(5):226-30

Authors: Xie J, Wang Q, Wang Q, Yao H, Wen L, Ma L, Wu D, Chen S

Abstract

Deletions affecting the B-cell translocation gene 1 (BTG1) have recently been reported in 9% of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and occur even more frequently in ETV6-RUNX1-positive and BCR-ABL1-positive subgroups. To investigate whether the BTG1 deletions occur in other BCR-ABL1-positive acute leukemias besides BCP-ALL, we analyzed 44 leukemia cases harboring the BCR-ABL1 transcript [32 BCP-ALL, six mixed-phenotype acute leukemia (MPAL), and six chronic myeloid leukemia in B-lineage blast crisis (CML-BC)] by array-based comparative genomic hybridization and reverse transcription-PCR. BTG1 deletions were present in 31.8% of BCR-ABL1-positive acute leukemia patients, including 31.3% of BCP-ALL (10/32), 33.3% of MPAL (2/6), and 33.3% of CML-BC (B-lineage) (2/6) patients. Of note, the intragenic deletion breakpoints, mapping to 5 different positions at the proximal end of the breakpoint, clustered tightly within exon 2 of BTG1, which were located within a stretch of 20 bp from nucleotide 284 to nucleotide 304 and led to truncated BTG1 transcripts. There were no significant differences in the median white blood cell count, hemoglobin concentration, platelet count, bone marrow blast count, sex, age, or overall complete remission rate between patients with and without BTG1 deletions. Taken together, our data suggest that BTG1 deletions might play a role in leukemogenesis of BCP-ALL as well as of BCR-ABL1-positive MPAL and CML-BC (B-lineage).

PMID: 24998463 [PubMed - indexed for MEDLINE]

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Ikaros transcripts Ik6/10 and levels of full-length transcript are critical for chronic myeloid leukaemia blast crisis transformation.

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Ikaros transcripts Ik6/10 and levels of full-length transcript are critical for chronic myeloid leukaemia blast crisis transformation.

Leukemia. 2014 Aug;28(8):1745-7

Authors: Wang L, Howarth A, Clark RE

PMID: 24618732 [PubMed - indexed for MEDLINE]

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BCR-ABL1-positive microvesicles transform normal hematopoietic transplants through genomic instability: implications for donor cell leukemia.

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BCR-ABL1-positive microvesicles transform normal hematopoietic transplants through genomic instability: implications for donor cell leukemia.

Leukemia. 2014 Aug;28(8):1666-75

Authors: Zhu X, You Y, Li Q, Zeng C, Fu F, Guo A, Zhang H, Zou P, Zhong Z, Wang H, Wu Y, Li Q, Kong F, Chen Z

Abstract

Malignant transformation of normal hematopoietic transplants induced by residual leukemia cells is considered as a pivotal mechanism of donor cell leukemia (DCL). The effects of leukemia cell-derived microvesicles (MVs) in this transformation were examined. We found that MVs derived from K562 leukemia cells contained the breakpoint cluster region-Abelson leukemia gene human homolog 1 (BCR-ABL1) mRNA. Following incubation with BCR-ABL1-positive MVs, mononuclear cells derived from normal transplants exhibited a leukemia-like malignant phenotype both in vitro and in vivo. Horizontal transfer of BCR-ABL1 mRNA from MVs into the recipient cells was critical to the transformation. Relative genomic instability was observed and considered the main mechanism in the recipient cells. MVs contributed to genomic instability by two distinct pathways: via consequent overexpression of activation-induced cytidine deaminase and reactive oxygen species, which mediated DNA breakage and recombination; and via upregulation of methyltransferases and global DNA hypermethylation. We demonstrated that BCR-ABL1-positive MVs could initiate malignant transformation of normal hematopoietic transplants through genomic instability, which might serve as a convenient and operable model for investigating leukemogenesis, especially for DCL. Furthermore, MVs themselves could act as an early warning indicator and a novel tool to detect and prevent the occurrence of DCL.

PMID: 24480987 [PubMed - indexed for MEDLINE]

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Total Synthesis and Determination of the Absolute Configuration of Rakicidin A.

Posted by rob on October 7, 2014 under Uncategorized | Comments are off for this article

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Total Synthesis and Determination of the Absolute Configuration of Rakicidin A.

J Am Chem Soc. 2014 Oct 6;

Authors: Sang F, Li D, Sun X, Cao X, Wang L, Sun J, Sun B, Wu L, Yang G, Chu X, Wang J, Dong C, Geng Y, Jiang H, Long H, Chen S, Wang G, Zhang S, Zhang Q, Chen Y

Abstract

Rakicidin A is a cyclic depsipeptide that has exhibited unique growth inhibitory activity against chronic myelogenous leukemia stem cells. Furthermore, rakicidin A has five chiral centers with unknown stereochemical assignment, and thus, can be represented by one of 32 possible stereoisomers. To predict the most probable stereochemistry of rakicidin A, calculations and structural comparison with natural cyclic depsipeptides were applied. A total synthesis of the proposed structure was subsequently completed, and highlighted by the creation of a sterically hindered ester bond (C1-C15) through trans-acylation from an easily established isomer (C1-C13). The analytic data of the synthetic target was consistent with that of natural rakicidin A, and then the absolute configuration of rakicidin A was assigned as 2S, 3S, 14S, 15S, 16R. This work suggests strategies for the determination of unknown chiral centers in other cyclic depsipeptides, such as rakicidin B, C, D, BE-43547 and vinylamycin, and facilitates the investigations of rakicidin A as an anti-cancer stem cell agent.

PMID: 25286338 [PubMed - as supplied by publisher]

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Overcoming Treatment Challenges in Imatinib-Resistant Chronic Myelogenous Leukemia.

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Overcoming Treatment Challenges in Imatinib-Resistant Chronic Myelogenous Leukemia.

Leuk Lymphoma. 2014 Oct 6;:1-6

Authors: Curi DA, Beauchamp EM, Platanias LC

PMID: 25284498 [PubMed - as supplied by publisher]

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Genetic analysis and clinical picture of severe congenital neutropenia in Israel.

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Genetic analysis and clinical picture of severe congenital neutropenia in Israel.

Pediatr Blood Cancer. 2014 Oct 4;

Authors: Lebel A, Yacobovich J, Krasnov T, Koren A, Levin C, Kaplinsky C, Ravel-Vilk S, Laor R, Attias D, Barak AB, Shtager D, Stein J, Kuperman A, Miskin H, Dgany O, Giri N, Alter BP, Tamary H

Abstract

BACKGROUND: The relative frequency of mutated genes among patients with severe congenital neutropenia (SCN) may differ between various ethnic groups. To date, few population-based genetic studies have been reported. This study describes the genetic analysis of 32 Israeli patients with SCN.

PROCEDURES: Clinical data were retrieved from the prospective Israeli Inherited Bone Marrow Failure Registry. Recruitment included living and deceased patients who were diagnosed between 1982 and 2012, for whom molecular diagnosis was performed. ELANE, HAX1 and G6PC3 genes were sequenced in all patients, and GFI-1 and WAS genes were sequenced if other genes were wildtype.

RESULTS: Eleven patients (34%) had heterozygous mutations in ELANE (10 kindreds), eight (25%) had homozygous mutations in G6PC3 (5 kindreds) and 13 (41%) had no detected mutations. No patients had mutations in HAX1 or WAS. Four of the eight patients with G6PC3 mutations had congenital anomalies. The probability of survival for all patients was 50% at age of 18. Deaths were mainly due to sepsis (5 patients, 4/5 not responding to G-CSF, none with G6PC3 mutation). Two patients developed acute myelogenous leukemia (AML) and one myelodysplastic syndrome (MDS), none with G6PC3 mutation.

CONCLUSIONS: We found a unique pattern of SCN mutations in Israel with homozygous G6PC3 mutations in eight (25%) patients, the highest frequency described so far. HAX1 mutations, reported mainly in Sweden and Iran, were absent. Patients with G6PC3 mutations had congenital anomalies, appeared to have a better response to G-CSF, and so far have not developed AML or MDS. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.

PMID: 25284454 [PubMed - as supplied by publisher]

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Incidence of Bcr-Abl kinase domain mutations in imatinib refractory chronic myeloid leukemia patients from South India.

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Incidence of Bcr-Abl kinase domain mutations in imatinib refractory chronic myeloid leukemia patients from South India.

Tumour Biol. 2014 Jul;35(7):7187-93

Authors: Kagita S, Uppalapati S, Jiwatani S, Linga VG, Gundeti S, Nagesh N, Digumarti R

Abstract

Mutations in the Bcr-Abl kinase domain (KD) are a major cause for acquired resistance to imatinib (IM) treatment and have been associated with progression and poor prognosis in chronic myeloid leukemia patients. The present study includes 63 patients resistant to standard imatinib dose of 400 mg according to ELN guidelines. Direct sequencing method is used for mutational analysis. The present study revealed 15 exonic mutations in 46.03 % of patients; among them, seven cases (24.13 %) had multiple mutations. Mutations were found to be higher in sokal high- (45.0 %) and intermediate- (68.42 %) compared to low-risk (29.16 %) group. Mutations were observed in 38.09 % of patients with EUTOS (European Treatment and Outcome Study) high risk and in 50.0 % with low risk. The frequency of mutations was 50.0 % in advanced phase, 47.36 % in late chronic-phase, and 43.33 % in chronic-phase patients. 42.10 % of patients with primary resistance and 52.0 % with secondary resistance had mutations. P-loop and T315I mutations were associated with poor survival in advanced phase patients (85.71 %) (P = 0.03). No significant variation was observed with Bcr-Abl transcript levels between the patients with the presence or absence of mutations (P = 0.73). Bcr-Abl levels were found to be significantly elevated in P-loop and T315I mutation carriers (P = 0.001) and also in T315I mutation-positive patients (P = 0.01). P-loop mutations and T315I are frequent in advanced phases and strongly associated with poor prognosis and survival. Hence, the identification of mutations in IM-resistant CML patients will help in treatment optimization with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs).

PMID: 24763825 [PubMed - indexed for MEDLINE]

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The occurrence of second neoplasms after treatment with tyrosine kinase inhibitors for chronic myeloid leukemia.

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The occurrence of second neoplasms after treatment with tyrosine kinase inhibitors for chronic myeloid leukemia.

Leuk Lymphoma. 2014 Feb;55(2):453-6

Authors: Togasaki-Yoshimoto E, Shono K, Onoda M, Yokota A

PMID: 23697842 [PubMed - indexed for MEDLINE]

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International development of an EORTC questionnaire for assessing health-related quality of life in chronic myeloid leukemia patients: the EORTC QLQ-CML24.

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International development of an EORTC questionnaire for assessing health-related quality of life in chronic myeloid leukemia patients: the EORTC QLQ-CML24.

Qual Life Res. 2014 Apr;23(3):825-36

Authors: Efficace F, Baccarani M, Breccia M, Saussele S, Abel G, Caocci G, Guilhot F, Cocks K, Naeem A, Sprangers M, Oerlemans S, Chie W, Castagnetti F, Bombaci F, Sharf G, Cardoni A, Noens L, Pallua S, Salvucci M, Nicolatou-Galitis O, Rosti G, Mandelli F

Abstract

BACKGROUND: Health-related quality of life (HRQOL) is a key aspect for chronic myeloid leukemia (CML) patients. The aim of this study was to develop a disease-specific HRQOL questionnaire for patients with CML to supplement the European Organization for Research and Treatment of Cancer (EORTC)-QLQ C30.

PATIENTS AND METHODS: The process followed a predefined and systematic stepwise iterative process as defined by the EORTC guidelines for questionnaire development. The process was divided into 3 phases: (1) generation of relevant HRQOL issues, (2) operationalization of the HRQOL issues into a set of items, and (3) pretesting the questionnaire for relevance and acceptability. Descriptive statistics and psychometric analyses were also performed.

RESULTS: Overall, 655 CML patients were enrolled in 10 countries including the USA and countries in Europe and Asia. Interviews with health-care professionals experienced in CML (n = 59) were also conducted. Results from the interviews, clinical experiences, and statistical analyses were used to develop the EORTC QLQ-CML24. The final module consists of 24 items assessing the following aspects: symptom burden, impact on daily life and on worry/mood, body image problems, and satisfaction with care and with social life. Internal consistency, assessed with Cronbach’s alpha coefficients, ranged from 0.73 to 0.83 for the proposed scales.

CONCLUSION: The EORTC QLQ-CML24 is an internationally developed HRQOL questionnaire for CML patients, and its implementation in clinical research and practice can provide important information to facilitate clinical decision-making.

PMID: 24026634 [PubMed - indexed for MEDLINE]

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