Superiority of allogeneic hematopoietic stem cell transplantation to nilotinib and dasatinib for adult patients with chronic myelogenous leukemia in the accelerated phase.

Posted by rob on June 24, 2015 under Uncategorized | Comments are off for this article

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Superiority of allogeneic hematopoietic stem cell transplantation to nilotinib and dasatinib for adult patients with chronic myelogenous leukemia in the accelerated phase.

Front Med. 2015 Jun 22;

Authors: Xu L, Zhu H, Hu J, Wu D, Jiang H, Jiang Q, Huang X

Abstract

In the tyrosine kinase inhibitor (TKI) era, imatinib is the first-line therapy for patients with chronic myeloid leukemia (CML) in chronic or accelerated phase. Although second-generation TKIs (TKI2), including dasatinib and nilotinib, are appropriate treatment regimens for patients with disease that progressed to accelerated phase following imatinib therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy. This study retrospectively analyzed the efficacy of TKI2 and HSCT for treatment of CML in accelerated phase. Ninety-three patients with CML registered in the Chinese CML alliance database from February 2001 to February 2014 were enrolled and divided into the TKI2 (n = 33) and allo-HSCT (n = 60) groups. In the TKI2 group, 26 and 7 patients received nilotinib and dasatinib, respectively, as initial TKI2 and 11 patients transferred to the alternative TKI2 after failure to one TKI2. In the allo-HSCT group, 22 (36.7%), 35 (58.3%), and 3 (10%) patients underwent allo-HSCT from an HLA-matched sibling donor, HLA mismatched/haploidentical donor, and unrelated donor, respectively. All patients in the HSCT group were engrafted. Overall, 69.7%, 48.5%, and 45.5% of patients presented hematological, cytogenetic, and major molecular responses, respectively, to at least one of TKI2. All 60 patients (100%) achieved CHR and cytogenetic response in the HSCT group. Patients in the TKI2 group exhibited lower 5-year overall survival rate (42.9% vs. 86.4%, P = 0.002), 5-year event-free survival rate (14.3% vs. 76.1%, P < 0.001), and 5-year progression-free survival (28.6% vs. 78.1%, P < 0.001) than those in the allo-HSCT group. Multivariate analysis showed that male sex and TKI2 therapy were predictors of poor overall survival, whereas hemoglobin < 100 g/L and TKI2 therapy were predictors of poor event-free survival and progression-free survival. These results indicated that allo-HSCT may be superior to nilotinib and dasatinib for adult patients with CML in accelerated phase.

PMID: 26100855 [PubMed - as supplied by publisher]

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Cardiovascular risk assessments in chronic myeloid leukemia allow identification of patients at high risk of cardiovascular events during treatment with nilotinib.

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Cardiovascular risk assessments in chronic myeloid leukemia allow identification of patients at high risk of cardiovascular events during treatment with nilotinib.

Am J Hematol. 2015 May;90(5):E100-1

Authors: Breccia M, Colafigli G, Molica M, Alimena G

PMID: 25683643 [PubMed - indexed for MEDLINE]

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shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance.

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shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance.

Blood. 2015 Mar 12;125(11):1772-81

Authors: Khorashad JS, Eiring AM, Mason CC, Gantz KC, Bowler AD, Redwine HM, Yu F, Kraft IL, Pomicter AD, Reynolds KR, Iovino AJ, Zabriskie MS, Heaton WL, Tantravahi SK, Kauffman M, Shacham S, Chenchik A, Bonneau K, Ullman KS, O’Hare T, Deininger MW

Abstract

The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting ?5000 cell signaling genes into K562(R), a CML cell line with BCR-ABL1 kinase-independent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562(R) cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34(+) cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34(+) cells from normal cord blood or from a patient harboring the BCR-ABL1(T315I) mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML.

PMID: 25573989 [PubMed - indexed for MEDLINE]

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Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase.

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Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase.

J Cancer Res Clin Oncol. 2015 May;141(5):887-99

Authors: Machova Polakova K, Kulvait V, Benesova A, Linhartova J, Klamova H, Jaruskova M, de Benedittis C, Haferlach T, Baccarani M, Martinelli G, Stopka T, Ernst T, Hochhaus A, Kohlmann A, Soverini S

Abstract

PURPOSE: Here, we studied whether amplicon next-generation deep sequencing (NGS) could improve the detection of emerging BCR-ABL1 kinase domain mutations in chronic phase chronic myeloid leukemia (CML) patients under tyrosine kinase inhibitor (TKI) treatment and discussed the clinical relevance of such sensitive mutational detection.

METHODS: For NGS data evaluation including extraction of biologically relevant low-level variants from background error noise, we established and applied a robust and versatile bioinformatics approach.

RESULTS: Results from a retrospective longitudinal analysis of 135 samples of 15 CML patients showed that NGS could have revealed emerging resistant mutants 2-11 months earlier than conventional sequencing. Interestingly, in cases who later failed first-line imatinib treatment, NGS revealed that TKI-resistant mutations were already detectable at the time of major or deeper molecular response. Identification of emerging mutations by NGS was mirrored by BCR-ABL1 transcript level expressed either fluctuations around 0.1 %(IS) or by slight transcript level increase. NGS also allowed tracing mutations that emerged during second-line TKI therapy back to the time of switchover. Compound mutants could be detected in three cases, but were not found to outcompete single mutants.

CONCLUSIONS: This work points out, that next-generation deep sequencing, coupled with a robust bioinformatics approach for mutation calling, may be just in place to ensure reliable detection of emerging BCR-ABL1 mutations, allowing early therapy switch and selection of the most appropriate therapy. Further, prospective assessment of how to best integrate NGS in the molecular monitoring and clinical decision algorithms is warranted.

PMID: 25367136 [PubMed - indexed for MEDLINE]

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Evidence for the persistence of an active endogenous retrovirus (ERVE) in humans.

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Evidence for the persistence of an active endogenous retrovirus (ERVE) in humans.

Genetica. 2014 Oct;142(5):451-60

Authors: Naveira H, Bello X, Abal-Fabeiro JL, Maside X

Abstract

Transposable elements (TEs) account for nearly half (44 %) of the human genome. However, their overall activity has been steadily declining over the past 35-50 million years, so that <0.05 % of TEs are presumably still “alive” (potentially transposable) in human populations. All the active elements are retrotransposons, either autonomous (LINE-1 and possibly the endogenous retrovirus ERVK), or non-autonomous (Alu and SVA, whose transposition is dependent on the LINE-1 enzymatic machinery). Here we show that a lineage of the endogenous retrovirus ERVE was recently engaged in ectopic recombination events and may have at least one potentially fully functional representative, initially reported as a novel retrovirus isolated from blood cells of a Chinese patient with chronic myeloid leukemia, which bears signals of positive selection on its envelope region. Altogether, there is strong evidence that ERVE should be included in the short list of potentially active TEs, and we give clues on how to identify human specific insertions of this element that are likely to be segregating in some of our populations.

PMID: 25192754 [PubMed - indexed for MEDLINE]

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Time-dependent influence of cell membrane permeability on MR diffusion measurements.

Posted by rob on June 23, 2015 under Uncategorized | Comments are off for this article

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Time-dependent influence of cell membrane permeability on MR diffusion measurements.

Magn Reson Med. 2015 Jun 11;

Authors: Li H, Jiang X, Xie J, McIntyre JO, Gore JC, Xu J

Abstract

PURPOSE: To investigate the influence of cell membrane permeability on diffusion measurements over a broad range of diffusion times.

METHODS: Human myelogenous leukemia K562 cells were cultured and treated with saponin to selectively alter cell membrane permeability, resulting in a broad physiologically relevant range of 0.011-0.044 ?m/ms. Apparent diffusion coefficient (ADC) values were acquired with the effective diffusion time (?eff ) ranging from 0.42 to 3000 ms. Cosine-modulated oscillating gradient spin echo (OGSE) measurements were performed to achieve short ?eff from 0.42 to 5 ms, while stimulated echo acquisitions were used to achieve long ?eff from 11 to 2999 ms. Computer simulations were also performed to support the experimental results.

RESULTS: Both computer simulations and experiments in vitro showed that the influence of membrane permeability on diffusion MR measurements is highly dependent on the choice of diffusion time, and it is negligible only when the diffusion time is at least one order of magnitude smaller than the intracellular exchange lifetime.

CONCLUSION: The influence of cell membrane permeability on the measured ADCs is negligible in OGSE measurements at moderately high frequencies. By contrast, cell membrane permeability has a significant influence on ADC and quantitative diffusion measurements at low frequencies such as those sampled using conventional pulsed gradient methods. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

PMID: 26096552 [PubMed - as supplied by publisher]

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Intracerebral Granulocytic Sarcoma in recurrence of Chronic Myeloid Leukemia.

Posted by rob on June 20, 2015 under Uncategorized | Comments are off for this article

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Intracerebral Granulocytic Sarcoma in recurrence of Chronic Myeloid Leukemia.

Arq Neuropsiquiatr. 2015 Jan;73(1):68

Authors: Brito AB, Reis F, Palma AL, Lima CS

PMID: 25608133 [PubMed - indexed for MEDLINE]

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The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas.

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The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas.

Genome Biol. 2014;15(7):417

Authors: Saraconi G, Severi F, Sala C, Mattiuz G, Conticello SG

Abstract

BACKGROUND: The AID/APOBECs are deaminases that act on cytosines in a diverse set of pathways and some of them have been linked to the onset of genetic alterations in cancer. Among them, APOBEC1 is the only family member to physiologically target RNA, as the catalytic subunit in the Apolipoprotein B mRNA editing complex. APOBEC1 has been linked to cancer development in mice but its oncogenic mechanisms are not yet well understood.

RESULTS: We analyze whether expression of APOBEC1 induces a mutator phenotype in vertebrate cells, likely through direct targeting of genomic DNA. We show its ability to increase the inactivation of a stably inserted reporter gene in a chicken cell line that lacks any other AID/APOBEC proteins, and to increase the number of imatinib-resistant clones in a human cellular model for chronic myeloid leukemia through induction of mutations in the BCR-ABL1 fusion gene. Moreover, we find the presence of an AID/APOBEC mutational signature in esophageal adenocarcinomas, a type of tumor where APOBEC1 is expressed, that mimics the one preferred by APOBEC1 in vitro.

CONCLUSIONS: Our findings suggest that the ability of APOBEC1 to trigger genetic alterations represents a major layer in its oncogenic potential. Such APOBEC1-induced mutator phenotypes could play a role in the onset of esophageal adenocarcinomas. APOBEC1 could be involved in cancer promotion at the very early stages of carcinogenesis, as it is highly expressed in Barrett’s esophagus, a condition often associated with esophageal adenocarcinoma.

PMID: 25085003 [PubMed - indexed for MEDLINE]

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Chronic myelogenous leukemia in patients with MPL or JAK2 mutation-positive myeloproliferative neoplasm.

Posted by rob on June 19, 2015 under Uncategorized | Comments are off for this article

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Chronic myelogenous leukemia in patients with MPL or JAK2 mutation-positive myeloproliferative neoplasm.

Int J Lab Hematol. 2015 Jun 18;

Authors: Chen Z, Wang W, Verstovsek S, Cortes JE, Medeiros LJ, Hu S

PMID: 26086872 [PubMed - as supplied by publisher]

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A Single Center Experience for Antifungal Prophylaxis in Patients with Acute Myelogenous Leukemia.

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A Single Center Experience for Antifungal Prophylaxis in Patients with Acute Myelogenous Leukemia.

Indian J Hematol Blood Transfus. 2015 Sep;31(3):339-45

Authors: Metan G, Türe Z, Pala Ç, Kaynar L, Y?ld?r?m A, Elmal? F, Tutar N, Yozgat N, Eser B

Abstract

We aimed to provide real-life information about the effectivity of different types of primary antifungal prophylaxis (AFP) in patients with acute myeloid leukemia (AML). Records of AML patients who received remission-induction chemotherapy between June 2010 and February 2013 were retrospectively reviewed. A total of 85 AML remission-induction chemotherapy cycles were identified in 80 patients. Fluconazole prophylaxis (FP) was administered in 29 cycles, and posaconazole prophylaxis was given in 56 cycles. Failure in the AFP was observed in 45 (57.9 %) out of 85 cycles. Any type of invasive fungal diseases were detected in 15 (26.8 %) out of 56 cycles receiving posaconazole and 15 (51.7 %) out of 29 cycles receiving fluconazole (p = 0.023). Relapsing or refractory AML, longer duration of neutropenia and FP were more common in patients with AFP failure. Multivariate logistic regression analysis showed that type of AFP (odds ratio (OR) 3.63; 95 % confidence interval (CI) 1.19-11.07), presence of neutropenia longer than 21 days (OR 3.96; 95 % CI 1.36-11.46), and refractory or relapsing AML (OR 6.09; 95 % CI 2.09-17.73) were independent factors associated with failure of AFP. We observed superiority of posaconazole on fluconazole in the prophylaxis of AML patients receiving remission-induction chemotherapy.

PMID: 26085718 [PubMed]

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CALR-mutated essential thrombocythemia evolving to chronic myeloid leukemia with coexistent CALR mutation and BCR-ABL translocation.

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CALR-mutated essential thrombocythemia evolving to chronic myeloid leukemia with coexistent CALR mutation and BCR-ABL translocation.

Blood. 2015 Apr 2;125(14):2309-11

Authors: Bonzheim I, Mankel B, Klapthor P, Schmidt J, Hinrichsen T, Wachter O, Fend F, Quintanilla-Martinez L

PMID: 25838280 [PubMed - indexed for MEDLINE]

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Morgana acts as an oncosuppressor in chronic myeloid leukemia.

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Morgana acts as an oncosuppressor in chronic myeloid leukemia.

Blood. 2015 Apr 2;125(14):2245-53

Authors: Di Savino A, Panuzzo C, Rocca S, Familiari U, Piazza R, Crivellaro S, Carrà G, Ferretti R, Fusella F, Giugliano E, Camporeale A, Franco I, Miniscalco B, Cutrin JC, Turco E, Silengo L, Hirsch E, Rege-Cambrin G, Gambacorti-Passerini C, Pandolfi PP, Papotti M, Saglio G, Tarone G, Morotti A, Brancaccio M

Abstract

We recently described morgana as an essential protein able to regulate centrosome duplication and genomic stability, by inhibiting ROCK. Here we show that morgana (+/-) mice spontaneously develop a lethal myeloproliferative disease resembling human atypical chronic myeloid leukemia (aCML), preceded by ROCK hyperactivation, centrosome amplification, and cytogenetic abnormalities in the bone marrow (BM). Moreover, we found that morgana is underexpressed in the BM of patients affected by atypical CML, a disorder of poorly understood molecular basis, characterized by nonrecurrent cytogenetic abnormalities. Morgana is also underexpressed in the BM of a portion of patients affected by Philadelphia-positive CML (Ph(+) CML) caused by the BCR-ABL oncogene, and in this condition, morgana underexpression predicts a worse response to imatinib, the standard treatment for Ph(+) CML. Thus, morgana acts as an oncosuppressor with different modalities: (1) Morgana underexpression induces centrosome amplification and cytogenetic abnormalities, and (2) in Ph(+) CML, it synergizes with BCR-ABL signaling, reducing the efficacy of imatinib treatment. Importantly, ROCK inhibition in the BM of patients underexpressing morgana restored the efficacy of imatinib to induce apoptosis, suggesting that ROCK inhibitors, combined with imatinib treatment, can overcome suboptimal responses in patients in which morgana is underexpressed.

PMID: 25678499 [PubMed - indexed for MEDLINE]

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Patient empowerment in the management of chronic myeloid leukemia.

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Patient empowerment in the management of chronic myeloid leukemia.

Clin J Oncol Nurs. 2014 Apr;18(2):E12-8

Authors: Coleman M

Abstract

Patient empowerment is a patient-centered approach to care in which healthcare providers nurture patients’ innate abilities to self-manage and incorporate patient goals for therapy into the overall management plan. Standard care of chronic myeloid leukemia (CML) requires lifelong medication with oral therapy and regular follow-up. The success of CML treatment, therefore, depends on a high degree of patient involvement and motivation, as well as strong collaboration between patients and healthcare providers. Oncology nurses can support patients with CML from the time of diagnosis to the end of treatment to ensure they maintain high levels of involvement in their care. At the author’s center, patients who most actively collaborate with their physicians in treatment decisions take personal responsibility for the quality of their care and show good adherence to treatment. In the current article, the author discusses the potential effect of patient response to cancer diagnosis on clinical outlook and describes strategies in place at the cancer center to ensure that patients diagnosed with CML have the best chance at keeping their cancer under control.

PMID: 24675265 [PubMed - indexed for MEDLINE]

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Conversion, correction, and International Scale standardization: results From a Multicenter External Quality Assessment Study for BCR-ABL1 testing.

Posted by rob on June 17, 2015 under Uncategorized | Comments are off for this article

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Conversion, correction, and International Scale standardization: results From a Multicenter External Quality Assessment Study for BCR-ABL1 testing.

Arch Pathol Lab Med. 2015 Apr;139(4):522-9

Authors: Griffiths M, Patton SJ, Grossi A, Clark J, Paz MF, Labourier E, Labceutics International BCR-ABL1 Standardization Study Group

Abstract

CONTEXT: Monitoring BCR-ABL1 expression levels relative to clinically validated response criteria on the International Scale (IS) is vital in the optimal management of patients with chronic myeloid leukemia, yet significant variability remains across laboratories worldwide.

OBJECTIVE: To assess method performance, interlaboratory precision, and different IS standardization modalities in representative laboratories performing routine BCR-ABL1 testing.

DESIGN: Fifteen blinded test specimens with 5-level nominal BCR-ABL1 to ABL1 IS percentage ratios ranging from 5% to 0.0005% and 4-level secondary IS reference panels, the ARQ IS Calibrator Panels, were tested by relative quantitative polymerase chain reaction in 15 laboratories in 5 countries. Both raw and IS percentage ratios calculated by using local conversion factors (CFs) or analytic correction parameters (CPs) were collected and analyzed.

RESULTS: A total of 670 valid positive results were generated. BCR-ABL1 detection was associated with variable ABL1 quality metric passing rates (P < .001) and reached at least 0.01% in 13 laboratories. Intralaboratory precision was within 2.5-fold for all sample levels combined with a relative mean difference greater than 5-fold across laboratories. International Scale accuracy was increased by using both the CF and CP standardization methods. Classification agreement for major molecular response status was 90% after CF conversion and 93% after CP correction, with precision improved by 3-fold for the CP method.

CONCLUSIONS: Despite preanalytic and analytic differences between laboratories, conversion and correction are effective IS standardization methods. Validated secondary reference materials can facilitate global diffusion of the IS without the need to perform sample exchange and improve the accuracy and precision of BCR-ABL1 quantitative measurements, including at low levels of residual disease.

PMID: 25061833 [PubMed - indexed for MEDLINE]

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A safety and feasibility study of an allogeneic colon cancer cell vaccine administered with a granulocyte-macrophage colony stimulating factor-producing bystander cell line in patients with metastatic colorectal cancer.

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A safety and feasibility study of an allogeneic colon cancer cell vaccine administered with a granulocyte-macrophage colony stimulating factor-producing bystander cell line in patients with metastatic colorectal cancer.

Ann Surg Oncol. 2014 Nov;21(12):3931-7

Authors: Zheng L, Edil BH, Soares KC, El-Shami K, Uram JN, Judkins C, Zhang Z, Onners B, Laheru D, Pardoll D, Jaffee EM, Schulick RD

Abstract

BACKGROUND: Despite recent advances in earlier detection and improvements in chemotherapy, the 5-year survival rate of patients with metastatic colorectal carcinoma remains poor. Immunotherapy is a potentially effective therapeutic approach to the treatment of colorectal carcinoma. Preclinical studies have supported the antitumor activity of immunization with a granulocyte-macrophage colony-stimulating factor (GM-CSF) producing murine colon tumor cell vaccine.

METHODS: A novel colorectal cancer vaccine composed of irradiated, allogeneic human colon cancer cells and GM-CSF-producing bystander cells was developed and tested in combination with a single intravenous low dose of cyclophosphamide in a phase 1 study of patients with metastatic colorectal cancer.

RESULTS: A total of nine patients were enrolled onto and treated in this study. Six patients had a history of colorectal adenocarcinoma hepatic metastases and underwent curative metastasectomy, while three other patients had unresectable stage IV disease. This study demonstrates the safety and feasibility of this vaccine administered in patients with metastatic colorectal cancer. At last follow-up, the six patients who underwent curative metastasectomy survived longer than 36 months, and four of these six patients were without disease recurrence. Immunologic correlate results suggest that the GM-CSF-producing colon cancer vaccine enhances the production of anti-MUC1 antibodies.

CONCLUSIONS: This vaccine is feasible and safe. Future investigation of the efficacy and antitumor immunity of this vaccine is warranted.

PMID: 24943235 [PubMed - indexed for MEDLINE]

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[One case of corneal melting after instillation of bromfenac 0.09%].

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[One case of corneal melting after instillation of bromfenac 0.09%].

J Fr Ophtalmol. 2014 Oct;37(8):e125-7

Authors: Troumani Y, Beral L, Glatre F, Finke E, David T

PMID: 24838029 [PubMed - indexed for MEDLINE]

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Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage.

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Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage.

Leuk Lymphoma. 2014 Oct;55(10):2408-9

Authors: Donatelli C, Chongnarungsin D, Ashton R

PMID: 24467220 [PubMed - indexed for MEDLINE]

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Molecular relapse after allogeneic hematopoietic cell transplant for chronic myeloid leukemia: some long-term survivors appear to tolerate even lack of major molecular response.

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Molecular relapse after allogeneic hematopoietic cell transplant for chronic myeloid leukemia: some long-term survivors appear to tolerate even lack of major molecular response.

Leuk Lymphoma. 2014 Oct;55(10):2398-401

Authors: Shanavas M, Messner HA, Kamel-Reid S, Atenafu EG, Gupta V, Kuruvilla J, Kim DD, Uhm J, Lambie A, Ellis L, Lipton JH

PMID: 24428200 [PubMed - indexed for MEDLINE]

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Targeting bcr-abl transcripts with siRNAs in an imatinib-resistant chronic myeloid leukemia patient: challenges and future directions.

Posted by rob on June 16, 2015 under Uncategorized | Comments are off for this article

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Targeting bcr-abl transcripts with siRNAs in an imatinib-resistant chronic myeloid leukemia patient: challenges and future directions.

Methods Mol Biol. 2015;1218:277-92

Authors: Koldehoff M

Abstract

Within the recent years, RNA interference (RNAi) has become an almost standard method for in vitro knockdown of any target gene of interest. Now, one major focus is to further explore its potential therapeutic use. From the mechanism, it becomes clear that small interfering RNAs (siRNAs) play a pivotal role in triggering RNAi. This chapter describes the in vivo application of targeted non-virally delivered synthetic bcr-abl siRNA in a female patient with recurrent Philadelphia chromosome positive chronic myeloid leukemia (CML) resistant to imatinib (Y253F mutation) and chemotherapy after allogeneic hematopoietic stem cell transplantation. A remarkable inhibition of the overexpressed bcr-abl oncogene resulting in increased apoptosis of CML cells was found. In vivo siRNA application was well tolerated without any clinically adverse events. The current findings imply that the clinical application of synthetic siRNA is feasible and safe and has real potential for genetic-based therapies using synthetic non-viral carriers.

PMID: 25319658 [PubMed - indexed for MEDLINE]

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A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA.

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A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA.

Oncogene. 2015 Apr 2;34(14):1768-79

Authors: Guo G, Kang Q, Zhu X, Chen Q, Wang X, Chen Y, Ouyang J, Zhang L, Tan H, Chen R, Huang S, Chen JL

Abstract

Aberrant expression of long noncoding RNAs (lncRNAs) is associated with various human cancers. However, the role of lncRNAs in Bcr-Abl-mediated chronic myeloid leukemia (CML) is unknown. In this study, we performed a comprehensive analysis of lncRNAs in human CML cells using an lncRNA cDNA microarray and identified an lncRNA termed lncRNA-BGL3 that acted as a key regulator of Bcr-Abl-mediated cellular transformation. Notably, we observed that lncRNA-BGL3 was highly induced in response to disruption of Bcr-Abl expression or by inhibiting Bcr-Abl kinase activity in K562 cells and leukemic cells derived from CML patients. Ectopic expression of lncRNA-BGL3 sensitized leukemic cells to undergo apoptosis and inhibited Bcr-Abl-induced tumorigenesis. Furthermore, transgenic (TG) mice expressing lncRNA-BGL3 were generated. We found that TG expression of lncRNA-BGL3 alone in mice was sufficient to impair primary bone marrow transformation by Bcr-Abl. Interestingly, we identified that lncRNA-BGL3 was a target of miR-17, miR-93, miR-20a, miR-20b, miR-106a and miR-106b, microRNAs that repress mRNA of phosphatase and tensin homolog (PTEN). Further experiments demonstrated that lncRNA-BGL3 functioned as a competitive endogenous RNA for binding these microRNAs to cross-regulate PTEN expression. Additionally, our experiments have begun to address the mechanism of how lncRNA-BGL3 is regulated in the leukemic cells and showed that Bcr-Abl repressed lncRNA-BGL3 expression through c-Myc-dependent DNA methylation. Taken together, these results reveal that Bcr-Abl-mediated cellular transformation critically requires silence of tumor-suppressor lncRNA-BGL3 and suggest a potential strategy for the treatment of Bcr-Abl-positive leukemia.

PMID: 24837367 [PubMed - indexed for MEDLINE]

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