Limited efficacy of HLA-haploidentical peripheral blood stem cell infusion in treatment of elderly patients with acute myelogenous leukaemia.

Posted by rob on August 28, 2015 under Uncategorized | Comments are off for this article

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Limited efficacy of HLA-haploidentical peripheral blood stem cell infusion in treatment of elderly patients with acute myelogenous leukaemia.

Hematol Oncol. 2015 Aug 27;

Authors: Sustkova Z, Jeziskova I, Dvorakova D, Horky O, Semerad L, Weinbergerova B, Culen M, Mayer J, Racil Z

PMID: 26310695 [PubMed - as supplied by publisher]

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Qualitative and Quantitative Evaluation of the BCR-ABL Fusion Gene in Chronic Myelogenous Leukemia by Flourescence In Situ Hybridization and Molecular Genetic Methods.

Posted by rob on August 27, 2015 under Uncategorized | Comments are off for this article

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Qualitative and Quantitative Evaluation of the BCR-ABL Fusion Gene in Chronic Myelogenous Leukemia by Flourescence In Situ Hybridization and Molecular Genetic Methods.

Genet Test Mol Biomarkers. 2015 Aug 26;

Authors: Sag SO, Yakut T, Gorukmez O, Gorukmez O, Ture M, Karkucak M, Gulten T, Ali R

Abstract

AIMS: Fluorescence in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (QRT-PCR) were used to diagnose or screen for minimal residual disease (MRD) in Philadelphia (Ph) chromosome-positive leukemia. We compared the diagnostic utility of FISH and QRT-PCR at various time points in the course of chronic myelogenous leukemia (CML) and to determine the mean initial values for patients whose QRT-PCR results were not known at the time of diagnosis.

RESULTS: We analyzed 135 results for 78 CML patients tested by FISH and QRT-PCR for the Ph chromosomal translocation. All newly diagnosed cases were positive by both methods. On follow-up following treatment, 1 case was FISH positive and QRT-PCR negative; 61 cases were FISH negative and QRT-PCR positive. Overall concordance was 54.1%. There was good concordance between QRT-PCR results and cytogenetic response categories.

CONCLUSIONS: We confirmed that QRT-PCR allows precise measurement of low levels of BCR-ABL transcripts and can serve as a sensitive indicator of MRD. We also demonstrated 100% correlation between QRT-PCR and FISH in newly diagnosed CML.

PMID: 26308792 [PubMed - as supplied by publisher]

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The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries.

Posted by rob on August 26, 2015 under Uncategorized | Comments are off for this article

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The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries.

Leukemia. 2015 Jun;29(6):1336-43

Authors: Hoffmann VS, Baccarani M, Hasford J, Lindoerfer D, Burgstaller S, Sertic D, Costeas P, Mayer J, Indrak K, Everaus H, Koskenvesa P, Guilhot J, Schubert-Fritschle G, Castagnetti F, Di Raimondo F, Lejniece S, Griskevicius L, Thielen N, Sacha T, Hellmann A, Turkina AG, Zaritskey A, Bogdanovic A, Sninska Z, Zupan I, Steegmann JL, Simonsson B, Clark RE, Covelli A, Guidi G, Hehlmann R

Abstract

This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100,000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.

PMID: 25783795 [PubMed - indexed for MEDLINE]

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Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.

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Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.

Leukemia. 2015 Jun;29(6):1331-5

Authors: Burchert A, Saussele S, Eigendorff E, Müller MC, Sohlbach K, Inselmann S, Schütz C, Metzelder SK, Ziermann J, Kostrewa P, Hoffmann J, Hehlmann R, Neubauer A, Hochhaus A

Abstract

A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.

PMID: 25712735 [PubMed - indexed for MEDLINE]

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Role of glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) genes in the development and progress of chronic myeloid leukemia and in the formation of response to imatinib therapy.

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Role of glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) genes in the development and progress of chronic myeloid leukemia and in the formation of response to imatinib therapy.

Bull Exp Biol Med. 2014 Dec;158(2):242-5

Authors: Ovsepyan VA, Luchinin AS, Zagoskina TP

Abstract

The effects of GSTM1 and GSTT1 gene deletion (“zero”) polymorphisms on the risk of chronic myeloid leukemia development and progress and on response to imatinib monotherapy were studied in the representatives of the Russian nationality in the Vyatka region of Russia. Homozygotic carriership of GSTT1 “zero” allele was associated with a 3.66 times higher risk of chronic myeloid leukemia development in residents of the Vyatka region (OR=3.66, 95% CI=2.12-6.30; p<0.0001). Combinations of the “zero” GSTM1 and GSTT1 genotypes were risk factors indicating the probable disease progress and failure of high cytogenetic response after 12 months of imatinib therapy (400 mg daily).

PMID: 25432281 [PubMed - indexed for MEDLINE]

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Aggregates of pseudo-Gaucher cells after treatment of chronic myeloid leukemia in blastic phase.

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Aggregates of pseudo-Gaucher cells after treatment of chronic myeloid leukemia in blastic phase.

Int J Hematol. 2015 Jan;101(1):3-4

Authors: Helbig G, Janikowska A, Kyrcz-Krzemien S

PMID: 25380681 [PubMed - indexed for MEDLINE]

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Assessment of Molecular Markers in AML Patients: A Hospital-Based Study in Lebanon.

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Assessment of Molecular Markers in AML Patients: A Hospital-Based Study in Lebanon.

Clin Lymphoma Myeloma Leuk. 2015 Jun;15 Suppl:S80-4

Authors: El Halabi L, Djaffar-Jureidini I, Hakime N, Saidy G, Chamseddine N

Abstract

BACKGROUND: In the past, research has been focused on elucidating the molecular genetics and epigenetic basis of acute myelogenous leukemia (AML). This has led to the change in the classification and management of AML patients. Because no molecular studies regarding AML characterization in Lebanese patients had yet been reported, we decided to determine in our institution the prevalence of the recurrent genetic rearrangements t(8;21), inv(16), t(15;17) and Fms-like (Suzanne McDonough feline sarcoma) tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) mutations.

MATERIALS AND METHODS: Fusion gene transcripts from chromosome aberrations were analyzed according to standardized reverse transcription polymerase chain reactions after the report of BIOMED-1 concerted action: investigation of minimal residual disease in acute leukemia. FLT3 and NPM1 mutations were screened using home-brew methodologies.

RESULTS: We reviewed 144 bone marrow samples from AML patients referred to Saint George Hospital for molecular and cytogenetic studies from September 2006 to July 2014. The male to female patient ratio was 1.34 to 1. We detected the inv(16) in 6 patients [4.2%] (type A, 5 [83%]; type D, 1 [17%]), t(8;21) in 7 patients [4.9%] (e5e2), and t(15;17) in 36 patients [25.0%] (24 [67%] breakpoint cluster region 1 (bcr1), 12 [33%] bcr3). Other chromosomal abnormalities (trisomy 8, complex karyotype, t(6;9),…) were found in 44 patients [31.4%] and 51 [35.5%] cases showed normal karyotype. Among the normal karyotypes, 6 patients [11.8%] were FLT3-positive (4 [67%] internal tandem duplication [ITD], 2 [33%] D835V), 8 [15.7%] had type A NPM1 mutation and 8 [15.7%] type A NPM1 and FLT3/ITD concomitantly.

CONCLUSION: Our results, except for the prevalence of acute promyelocytic leukemia, are concordant with those reported in the literature with approximately 35% of the patients cytogenetically normal. Testing patients with normal karyotype for other molecular markers such as CCAAT/enhancer-binding protein alpha mutations, isocitrate dehydrogenase 1/2 mutations, and mixed lineage leukemia rearrangements could therefore provide additional prognostic, predictive, and therapeutic values for AML patients.

PMID: 26297285 [PubMed - in process]

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Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome-Positive Leukemia: 25 Years’ Experience at Gustave Roussy Cancer Campus.

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Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome-Positive Leukemia: 25 Years’ Experience at Gustave Roussy Cancer Campus.

Clin Lymphoma Myeloma Leuk. 2015 Jun;15 Suppl:S129-40

Authors: Chamseddine AN, Willekens C, De Botton S, Bourhis JH

Abstract

The introduction of tyrosine kinase inhibitor (TKI) therapy has markedly reduced the use of allogeneic (allo) hematopoietic stem cell transplantation (HSCT), which is no longer standard practice in the first chronic phase in chronic myelogenous leukemia and is currently reserved after failure of TKI or in advanced phase of disease. We compared the outcome of Philadelphia chromosome-positive (Ph+) leukemia patients who received a first allo-HSCT in our center in both the pre-TKI era and the TKI era. The primary end point was to compare the 2 groups’ overall survival (OS), leukemia-free survival (LFS), cumulative incidence of nonrelapse mortality, and relapse incidence. The secondary end point was to underline in the TKI era the impact of the pretransplantation minimal residual disease (MRD) on the outcomes. A total of 69 patients with Ph+ leukemia were included and their outcomes analyzed. For the purpose of this analysis, we defined 2 groups: group A (n = 39) included patients treated in the pre-TKI era, treated from January 1989 until December 2001, and group B (n = 30) included patients treated in the TKI era, treated from January 2002 until December 2013. Additional analysis was performed in group B for whom detailed TKIs and MRD data were collected. The study took place in our cancer center in the department of HSCT, Villejuif, France. The median follow-up duration for group A was 116.1 months (range, 1.1 to 240.1 months) and for group B was 8.3 months (range, 3.5 to 141.7 months). At 3 years, the LFS and OS were higher in group B (respectively, 66% and 71%) than in group A (respectively, 63% and 57%) (P > .05). The LFS and OS at 3 years of the pretransplantation MRD-negative (< 0.01%) patients were significantly (P < .05) higher (respectively, 83% and 94%) than the pretransplantation MRD-positive patients (respectively, 43% and 46%). Our data, although statistically not significant, suggest better outcomes for Ph+ leukemia patients undergoing allo-HSCT in the TKI era. Mostly TKI does not adversely affect the transplantation outcomes and can be used successfully as a bridge to allo-HSCT, especially in advanced disease. In addition, we highlight the importance of obtaining deep pretransplantation MRD negativity.

PMID: 26297265 [PubMed - in process]

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Differences among young adults, adults and elderly chronic myeloid leukemia patients.

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Differences among young adults, adults and elderly chronic myeloid leukemia patients.

Ann Oncol. 2015 Jan;26(1):185-92

Authors: Castagnetti F, Gugliotta G, Baccarani M, Breccia M, Specchia G, Levato L, Abruzzese E, Rossi G, Iurlo A, Martino B, Pregno P, Stagno F, Cuneo A, Bonifacio M, Gobbi M, Russo D, Gozzini A, Tiribelli M, de Vivo A, Alimena G, Cavo M, Martinelli G, Pane F, Saglio G, Rosti G, GIMEMA CML Working Party

Abstract

BACKGROUND: The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage.

PATIENTS AND METHODS: To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period.

RESULTS: Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011).

CONCLUSIONS: The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome.

CLINICAL TRIAL NUMBERS: NCT00510926, NCT00514488, NCT00769327, NCT00481052.

PMID: 25361995 [PubMed - indexed for MEDLINE]

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Myelodysplastic syndromes: 2015 Update on diagnosis, risk-stratification and management.

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Myelodysplastic syndromes: 2015 Update on diagnosis, risk-stratification and management.

Am J Hematol. 2015 Sep;90(9):831-41

Authors: Garcia-Manero G

Abstract

DISEASE OVERVIEW: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy.

DIAGNOSIS: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, or molecular genetics is complementary but not diagnostic. Risk-stratification: Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow, and cytogenetic characteristics. The most commonly used system still is probably the International Prognostic Scoring System (IPSS). IPSS is being replaced by the new revised score IPSS-R.

RISK-ADAPTED THERAPY: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts, and more recently cytogenetic and mutational profiles. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia, and a chromosome 5 alteration. 5-Azacitidine and decitabine have activity in higher risk MDS. 5-Azacitidine has been shown to improve survival in higher risk MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic targets or aid in the selection of currently available agents. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation. Management of progressive or refractory disease: At the present time there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include participation in a clinical trial or cytarabine based therapy and stem cell transplantation. Am. J. Hematol. 90:832-841, 2015. © 2015 Wiley Periodicals, Inc.

PMID: 26294090 [PubMed - in process]

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Design of inhibitors of BCRP/ABCG2.

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Design of inhibitors of BCRP/ABCG2.

Future Med Chem. 2015 Aug 21;:1-7

Authors: Juvale K, Wiese M

Abstract

BCRP/ABCG2, a second member of ABC transporter subclass G, has been shown to be overexpressed in several solid tumors, acute myelogenous leukemia and chronic myeloid leukemia. A variety of chemically unrelated anticancer drugs have been found to be transported by ABCG2 leading to their lower intracellular accumulation and hence causing chemoresistance. Until now several efforts have been taken to identify potent and selective inhibitors of ABCG2. Recent studies carried out to deign BCRP inhibitors have been able to point out the effect of the substitution pattern in compound scaffolds on the potency, selectivity and cytotoxicity of ABCG2 inhibitors.

PMID: 26293476 [PubMed - as supplied by publisher]

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Successful unrelated stem cell transplantation in an infant with congenital acute myelogenous leukemia FAB M5 showing massive cutaneous infiltrations-A challenging multidisciplinary approach.

Posted by rob on August 21, 2015 under Uncategorized | Comments are off for this article

Successful unrelated stem cell transplantation in an infant with congenital acute myelogenous leukemia FAB M5 showing massive cutaneous infiltrations-A challenging multidisciplinary approach.

Pediatr Blood Cancer. 2015 Aug 20;

Authors: Lanz S, Schwinger W, Sovinz P, Lackner H, Resch B, Urlesberger B, Sipurzynski S, Urban C

Abstract

The multidisciplinary management of a male neonate presenting with congenital acute myelogenous leukemia of monoblastic phenotype is reported using conventional chemotherapy, high dose conditioning, and matched unrelated donor stem cell transplantation. These therapies were combined to add a graft versus leukemia effect to the treatment. Although chimerism studies showed a decrease of donor white blood cells, T-cells remained stable of allogeneic origin. We hypothesize that a continuous graft versus leukemia effect results in minimal residual disease negativity for now more than 18 months since stem cell transplantation. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

PMID: 26291692 [PubMed - as supplied by publisher]

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Chemopreventive effects of dietary eicosapentaenoic acid supplementation in an experimental myeloid leukemia.

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Chemopreventive effects of dietary eicosapentaenoic acid supplementation in an experimental myeloid leukemia.

Cancer Prev Res (Phila). 2015 Aug 19;

Authors: Finch ER, Kudva AK, Quickel MD, Goodfield LL, Kennett MJ, Whelan J, Paulson RF, Prabhu KS

Abstract

Current therapies for treatment of myeloid leukemia do not eliminate leukemia stem cells (LSC), leading to disease relapse. In this study, we supplemented mice with eicosapentaenoic acid (EPA, C20:5), a polyunsaturated omega-3 fatty acid, at pharmacological levels, to examine if the endogenous metabolite, cyclopentenone prostaglandin delta-12 PGJ3 (?12-PGJ3), was effective in targeting LSCs in experimental leukemia. EPA supplementation for eight weeks resulted in enhanced endogenous production of ?12-PGJ3 that was blocked by indomethacin, a cyclooxygenase inhibitor. Using a murine model of chronic myelogenous leukemia (CML) induced by bone marrow transplantation of BCR-ABL-expressing hematopoietic stem cells, mice supplemented with EPA showed a decrease in the LSC population, reduced splenomegaly and leukocytosis, when compared to mice on an oleic acid diet. Supplementation of CML mice carrying the T315I mutation (in BCR-ABL) with EPA resulted in a similar effect. Indomethacin blocked the EPA effect and increased the severity of BCR-ABL-induced CML and decreased apoptosis. ?12-PGJ3 rescued indomethacin-treated BCR-ABL mice and decreased LSCs. Inhibition of hematopoietic-prostaglandin D synthase (H-PGDS) by HQL-79 in EPA-supplemented CML mice also blocked the effect of EPA. In addition, EPA supplementation was effective in a murine model of acute myeloid leukemia. Supplemented mice exhibited a decrease in leukemia burden and a decrease in the LSC colony-forming unit (LSC-CFU). The decrease in LSCs was confirmed through serial transplantation assays in all disease models. The results support a chemopreventive role for EPA in myeloid leukemia, which is dependent on the ability to efficiently convert EPA to endogenous cyclooxygenase-derived prostanoids, including ?12-PGJ3.

PMID: 26290393 [PubMed - as supplied by publisher]

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Dipeptide species regulate p38MAPK-Smad3 signalling to maintain chronic myelogenous leukaemia stem cells.

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Dipeptide species regulate p38MAPK-Smad3 signalling to maintain chronic myelogenous leukaemia stem cells.

Nat Commun. 2015;6:8039

Authors: Naka K, Jomen Y, Ishihara K, Kim J, Ishimoto T, Bae EJ, Mohney RP, Stirdivant SM, Oshima H, Oshima M, Kim DW, Nakauchi H, Takihara Y, Kato Y, Ooshima A, Kim SJ

Abstract

Understanding the specific survival of the rare chronic myelogenous leukaemia (CML) stem cell population could provide a target for therapeutics aimed at eradicating these cells. However, little is known about how survival signalling is regulated in CML stem cells. In this study, we survey global metabolic differences between murine normal haematopoietic stem cells (HSCs) and CML stem cells using metabolomics techniques. Strikingly, we show that CML stem cells accumulate significantly higher levels of certain dipeptide species than normal HSCs. Once internalized, these dipeptide species activate amino-acid signalling via a pathway involving p38MAPK and the stemness transcription factor Smad3, which promotes CML stem cell maintenance. Importantly, pharmacological inhibition of dipeptide uptake inhibits CML stem cell activity in vivo. Our results demonstrate that dipeptide species support CML stem cell maintenance by activating p38MAPK-Smad3 signalling in vivo, and thus point towards a potential therapeutic target for CML treatment.

PMID: 26289811 [PubMed - in process]

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Inhibition of STAT3-interacting protein 1 (STATIP1) promotes STAT3 transcriptional up-regulation and imatinib mesylate resistance in the chronic myeloid leukemia.

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Inhibition of STAT3-interacting protein 1 (STATIP1) promotes STAT3 transcriptional up-regulation and imatinib mesylate resistance in the chronic myeloid leukemia.

BMC Cancer. 2014;14:866

Authors: Mencalha AL, Corrêa S, Salles D, Du Rocher B, Santiago MF, Abdelhay E

Abstract

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is an important transcriptional factor frequently associated with the proliferation and survival of a large number of distinct cancer types. However, the signaling pathways and mechanisms that regulate STAT3 activation remain to be elucidated.

METHODS: In this study we took advantage of existing cellular models for chronic myeloid leukemia resistance, western blot, in vitro signaling, real time PCR, flow cytometry approaches for cell cycle and apoptosis evaluation and siRNA assay in order to investigate the possible relationship between STATIP1, STAT3 and CML resistance.

RESULTS: Here, we report the characterization of STAT3 protein regulation by STAT3-interacting protein (STATIP1) in the leukemia cell line K562, which demonstrates constitutive BCR-ABL TK activity. K562 cells exhibit high levels of phosphorylated STAT3 accumulated in the nucleus and enhanced BCR-ABL-dependent STAT3 transcriptional activity. Moreover, we demonstrate that STATIP1 is not involved in either BCR-ABL or STAT3 signaling but that STATIP1 is involved in the down-regulation of STAT3 transcription levels; STATIP1-depleted K562 cells display increased proliferation and increased levels of the anti-apoptosis STAT3 target genes CCND1 and BCL-XL, respectively. Furthermore, we demonstrated that Lucena, an Imatinib (IM)-resistant cell line, exhibits lower STATIP1 mRNA levels and undergoes apoptosis/cell cycle arrest in response to STAT3 inhibition together with IM treatment. We provide evidence that STATIP1 siRNA could confer therapy resistance in the K562 cells. Moreover, analysis of CML patients showed an inverse expression of STAIP1 and STAT3 mRNA levels, ratifying that IM-resistant patients present low STATIP1/high STAT3 mRNA levels.

CONCLUSIONS: Our data suggest that STATIP1 may be a negative regulator of STAT3 and demonstrate its involvement in IM therapy resistance in CML.

PMID: 25417721 [PubMed - indexed for MEDLINE]

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Sequencing treatment in chronic myeloid leukemia: the first choice may be the hardest.

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Sequencing treatment in chronic myeloid leukemia: the first choice may be the hardest.

Clin Adv Hematol Oncol. 2014 Aug;12(8):502-8

Authors: Heaney ML

Abstract

Columbia University -Medical Center, New York, New York. The advent of tyrosine kinase inhibitors (TKIs) as primary treatment in chronic myeloid leukemia (CML) has greatly changed expectations of both physicians and patients. The use of imatinib has led not only to reliable cytogenetic responses, but also to deeper “molecular” responses that have brought long-term survival to a disease that was generally lethal in patients who were not candidates for stem cell transplantation. The more recent entrée of second-generation TKIs-nilotinib, dasatinib, bosutinib, and ponatinib-as well as the protein synthesis inhibitor omacetaxine, has provided access to more potent agents. These new drugs provide a safety net for patients whose disease does not respond to imatinib, but also create dilemmas for physicians treating CML patients. This review examines the evidence that informs choice of initial therapy, and discusses management options in the context of new goals of care, emerging toxicities, and the possibility of discontinuing treatment.

PMID: 25356574 [PubMed - indexed for MEDLINE]

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Parameterized SVM for personalized drug concentration prediction.

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Parameterized SVM for personalized drug concentration prediction.

Conf Proc IEEE Eng Med Biol Soc. 2013;2013:5789-92

Authors: You W, Simalatsar A, De Micheli G

Abstract

This paper proposes a parameterized Support Vector Machine (ParaSVM) approach for modeling the Drug Concentration to Time (DCT) curves. It combines the merits of Support Vector Machine (SVM) algorithm that considers various patient features and an analytical model that approximates the predicted DCT points and enables curve calibrations using occasional real Therapeutic Drug Monitoring (TDM) measurements. The RANSAC algorithm is applied to construct the parameter library for the relevant basis functions. We show an example of using ParaSVM to build DCT curves and then calibrate them by TDM measurements on imatinib case study.

PMID: 24111054 [PubMed - indexed for MEDLINE]

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Low socioeconomic status, adverse gene expression profiles, and clinical outcomes in hematopoietic stem cell transplant recipients.

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Low socioeconomic status, adverse gene expression profiles, and clinical outcomes in hematopoietic stem cell transplant recipients.

Clin Cancer Res. 2015 Aug 18;

Authors: Knight JM, Rizzo JD, Logan BR, Wang T, Arevalo JM, Ma J, Cole SW

Abstract

PURPOSE: Low socioeconomic status (SES) is associated with adverse outcomes among unrelated donor hematopoietic stem cell transplant (HCT) recipients, but the biological mechanisms contributing to this health disparity are poorly understood. Therefore, we examined whether social environment affects expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA), which involves up-regulation of pro-inflammatory genes and down-regulation of genes involved in type I IFN response and antibody synthesis.

EXPERIMENTAL DESIGN: We compared pre-transplant leukocyte CTRA gene expression between a group of 78 high vs. low SES recipients of unrelated donor HCT for acute myelogenous leukemia in first remission. Post hoc exploratory analyses also evaluated whether CTRA gene expression was associated with poor clinical outcomes.

RESULTS: Peripheral blood mononuclear cells collected pre-HCT from low SES individuals demonstrated significant CTRA up-regulation compared to matched HCT recipients of high SES. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity including increased CREB signaling and decreased IRF and GR signaling. High expression of the CTRA gene profile was also associated with increased relapse risk and decreased leukemia-free survival.

CONCLUSIONS: Low SES is associated with increased expression of the CTRA gene profile, and CTRA gene expression is associated with adverse HCT clinical outcomes. These findings provide a biologic framework within which to understand how social environmental conditions may influence immune function and clinical outcomes in allogeneic HCT.

PMID: 26286914 [PubMed - as supplied by publisher]

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Fatigue and an Elevated White Blood Cell Count.

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Fatigue and an Elevated White Blood Cell Count.

JAMA. 2015 Aug 11;314(6):617-8

Authors: Sellers MH, Dinner SN

PMID: 26262801 [PubMed - indexed for MEDLINE]

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Do we need more drugs for chronic myeloid leukemia?

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Do we need more drugs for chronic myeloid leukemia?

Immunol Rev. 2015 Jan;263(1):106-23

Authors: Holyoake TL, Helgason GV

Abstract

The introduction of protein tyrosine kinase inhibitors (TKIs) in 1998 transformed the management of chronic myeloid leukemia (CML), leading to significantly reduced mortality and improved 5 year survival rates. However, the CML community is faced with several clinical issues that need to be addressed. Ten to 15% of CML patients are diagnosed in advanced phase, and small numbers of chronic phase (CP) cases experience disease progression each year during treatment. For these patients, TKIs induce only transient responses and alternative treatment strategies are urgently required. Depending on choice of first line TKI, approximately 30% of CML CP cases show suboptimal responses, due to a combination of poor compliance, drug intolerance, and drug resistance, with approximately 50% of TKI-resistance caused by kinase domain mutations and the remainder due to unknown mechanisms. Finally, the chance of successful treatment discontinuation is on the order of only 10-20% related to disease persistence. Disease persistence is a poorly understood phenomenon; all CML patients have functional Philadelphia positive (Ph+) stem and progenitor cells in their bone marrows and continue to express BCR-ABL1 by DNA PCR, even when in very deep remission and following treatment discontinuation. What controls the maintenance of these persisting cells, whether it is necessary to fully eradicate the malignant clone to achieve cure, and how that might be approached therapeutically are open questions.

PMID: 25510274 [PubMed - indexed for MEDLINE]

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