Discovery of allosteric bcr-abl inhibitors from phenotypic screen to clinical candidate.

Posted by rob on November 19, 2014 under Uncategorized | Comments are off for this article

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Discovery of allosteric bcr-abl inhibitors from phenotypic screen to clinical candidate.

Methods Enzymol. 2014;548:173-88

Authors: Gray NS, Fabbro D

Abstract

The development of imatinib, an ATP-competitive inhibitor of the BCR-ABL oncoprotein, has revolutionized the treatment of chronic myelogenous leukemia (CML). Unfortunately, the leukemia eventually becomes resistant imatinib as a result of emergence of cells expressing drug insensitive BCR-ABL mutant proteins. This has motivated the development of several next-generation ATP-competitive drugs. This chapter describes the discovery and development of a complementary strategy involving inhibiting BCR-ABL by targeting an allosteric binding site. Compounds that bind to the myristate-binding pocket of BCR-ABL are able to induce formation of an “inactive” state and are able to overcome resistance mutations located in the ATP-binding pocket including the recalcitrant T315I “gatekeeper” mutation. Myristate-pocket inhibitors are also able to function synergistically with ATP-competitive inhibitors in cellular and murine models of CML and this dual inhibitory strategy is currently being investigated in the clinic.

PMID: 25399646 [PubMed - in process]

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Why is there so much therapy-related AML and MDS and so little therapy-related CML?

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Why is there so much therapy-related AML and MDS and so little therapy-related CML?

Leuk Res. 2014 Oct;38(10):1162-4

Authors: Gale RP, Hlatky L, Sachs RK, Radivoyevitch T

PMID: 25175829 [PubMed - indexed for MEDLINE]

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Downregulation of endogenous STAT3 augments tumoricidal activity of interleukin 15 activated dendritic cell against lymphoma and leukemia via TRAIL.

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Downregulation of endogenous STAT3 augments tumoricidal activity of interleukin 15 activated dendritic cell against lymphoma and leukemia via TRAIL.

Exp Cell Res. 2014 Oct 1;327(2):192-208

Authors: Hira SK, Mondal I, Bhattacharya D, Manna PP

Abstract

Effector functions in tumor resistance by dendritic cells (DCs) are less well characterized. In this study, we describe that the murine DCs upon stimulation with recombinant IL-15 in vitro or in vivo, expresses TNF superfamily member TRAIL which mediates cytotoxicity and growth inhibition against a murine lymphoma called Dalton lymphoma (DL) via apoptosis. Presence of tumor lysate or intact tumor cells significantly reduces the DC mediated tumoricidal effect, possibly via masking and down-regulating TRAIL in DCs. The antitumor effect of DC derived TRAIL was further augmented by deactivation of STAT3 in tumor cells by cucurbitacin I, which makes it more susceptible to DC derived TRAIL Treatment of tumor cells with cucurbitacin I upregulates TRAIL receptor expression in addition to activation of caspases. Compared to naïve DCs, DCs from tumor bearing mice are significantly impaired in TRAIL expression and consequent antitumor functions against DL which was partially restored by activation with IL-15 or LPS. Priming with recombinant IL-15 prolongs the survival of tumor bearing mice treated with cucurbitacin I. Naïve peripheral blood DCs derived from chronic myeloid leukemia (CML) patients have significant impairment in expression of TRAIL and consequent tumoricidal properties against TRAIL sensitive lymphoma cell lines and primary tumor cells compared to normal control.

PMID: 25139620 [PubMed - indexed for MEDLINE]

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Outcome prediction by the transcript level of BCR-ABL at 3 months in patients with chronic myeloid leukemia treated with imatinib–a single institution historical experience.

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Outcome prediction by the transcript level of BCR-ABL at 3 months in patients with chronic myeloid leukemia treated with imatinib–a single institution historical experience.

Leuk Res. 2014 Oct;38(10):1191-8

Authors: Yin XF, Ma QL, Mu QT, Shao L, Wang SS, Meng HT, Xu WL, Wang YG, Chen ZM, Chen FF, Jin J

Abstract

The BCR-ABL transcript level (? 10%) at 3 months after tyrosine kinase inhibitors can predict long term outcome in the patients with chronic myeloid leukemia in chronic phase (CML-CP). However, the significance of transcript level was still not determined in different risk groups of patients. A total of 299 patients with CML-CP were enrolled and stratified according to prior interferon-? (IFN) treatment, age, and interval time between diagnosis and imatinib treatment to investigate the prediction value of BCR-ABL transcript level for overall survival (OS), event-free survival (EFS), progression-free survival (PFS). Univariate and multivariate analysis proved that BCR-ABL transcript level at 3 months were associated with the treatment outcome. However, in the patients with prior IFN treatment, younger age, and longer interval between diagnosis and IM treatment, the predictive value of transcript value remain obscure in terms of EFS, PFS and OS, respectively, as well as cumulative incidence of PCyR, CCR, MMR and CMR. In conclusion, the transcript level of BCR-ABL at 3 months could serve as a predictive parameter, but should be used with caution.

PMID: 25115808 [PubMed - indexed for MEDLINE]

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Elderly CML patients’ treatment: considering not only physician’s judgment but also co-morbidity indexes.

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Elderly CML patients’ treatment: considering not only physician’s judgment but also co-morbidity indexes.

Leuk Res. 2014 Oct;38(10):1156-7

Authors: Sánchez-Guijo F

PMID: 25113280 [PubMed - indexed for MEDLINE]

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Molecular response in CML: where is the bar?

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Molecular response in CML: where is the bar?

Blood. 2014 Jul 24;124(4):469-71

Authors: Baccarani M, Soverini S

PMID: 25061165 [PubMed - indexed for MEDLINE]

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Age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival.

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Age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival.

Leuk Res. 2014 Oct;38(10):1173-6

Authors: Breccia M, Luciano L, Latagliata R, Castagnetti F, Ferrero D, Cavazzini F, Trawinska MM, Annunziata M, Stagno F, Tiribelli M, Binotto G, Crisà E, Musto P, Gozzini A, Cavalli L, Montefusco E, Iurlo A, Russo S, Cedrone M, Rossi AR, Pregno P, Endri M, Spadea A, Molica M, Giglio G, Celesti F, Sorà F, Storti S, D’Addosio A, Cambrin GR, Isidori A, Sica S, Abruzzese E, Speccha G, Rosti G, Alimena G

Abstract

We applied Charlson comorbidity index (CCI) stratification on a large cohort of chronic myeloid leukemia (CML) very elderly patients (>75 years) treated with imatinib, in order to observe the impact of concomitant diseases on both compliance and outcome. One hundred and eighty-one patients were recruited by 21 Italian centers. There were 95 males and 86 females, median age 78.6 years (range 75-93.6). According to Sokal score, 106 patients were classified as intermediate risk and 55 as high risk (not available in 20 patients). According to CCI stratification, 71 patients had score 0 and 110 a score ? 1. Imatinib standard dose was reduced at start of therapy (200-300 mg/day) in 68 patients independently from the evaluation of baseline comorbidities, but based only on physician judgement: 43.6% of these patients had score 0 compared to 34% of patients who had score ? 1. Significant differences were found in terms of subsequent dose reduction (39% of patients with score 0 compared to 53% of patients with score ? 1) and in terms of drug discontinuation due to toxicity (35% of patients with score 0 vs 65% of patients with score ? 1). We did not find significant differences as regards occurrence of hematologic side effects, probably as a consequence of the initial dose reduction: 39% of patients with score 0 experienced grade 3/4 hematologic toxicity (most commonly anemia) compared to 42% of patients with score ? 1. Independently from the initial dose, comorbidities again did not have an impact on development of grade 3/4 non-hematologic side effects (most commonly skin rash, muscle cramps and fluid retention): 62% of patients with score 0 compared to 52.5% of patients with score ? 1. Notwithstanding the reduced dose and the weight of comorbidities we did not find significant differences but only a trend in terms of efficacy: 66% of patients with score 0 achieved a CCyR compared to 54% of patients with score ? 1. Comorbidities appeared to have an impact on median OS (40.8 months for patients with score 0 vs 20.16 months for patients with score ? 1) on EFS and on non-CML death rate. Our results suggest that treatment of very elderly CML patients might be influenced by personal physician perception: evaluation at baseline of comorbidities according to CCI should improve initial decision-making in this subset of patients.

PMID: 25047978 [PubMed - indexed for MEDLINE]

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CIAPIN1 targets Na+/H+ exchanger 1 to mediate K562 chronic myeloid leukemia cells’ differentiation via ERK1/2 signaling pathway.

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CIAPIN1 targets Na+/H+ exchanger 1 to mediate K562 chronic myeloid leukemia cells’ differentiation via ERK1/2 signaling pathway.

Leuk Res. 2014 Sep;38(9):1117-25

Authors: Wang J, Xu H, Zhang H, Wang Q, Wang C, Zhang H, Lin Y, Ru Y, Liang H, Li Q, Pang T

Abstract

CIAPIN1 (cytokine-induced antiapoptotic inhibitor 1) was recently identified as an essential downstream effector of the Ras signaling pathway. However, its potential role in regulating myeloid differentiation remains unclear. In this study, we found depletion of CIAPIN1 by shRNAs led to granulocytic differentiation of K562 cells. Meanwhile, the decrease of NHE1 and up-regulation of phosphorylated ERK1/2 were observed after CIAPIN1 depletion. Interestingly, targeted inhibition of NHE1 further promoted the differentiation of K562 cells with CIAPIN1 silencing. Accordingly, ectopic expression of NHE1 reversed this phenotype. Furthermore, ERK1/2 inhibition with the chemical inhibitor, PD98059, abolished CIAPIN1 silencing-induced differentiation of K562 cells after NHE1 inhibition. Thus, our results revealed important mechanism that CIAPIN1 targeted NHE1 to mediate differentiation of K562 cells via ERK1/2 pathway. Our findings implied CIAPIN1 and NHE1 could be new targets in developing therapeutic strategies against leukemia.

PMID: 25043809 [PubMed - indexed for MEDLINE]

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Establishment and characterization of a rare atypical chronic myeloid leukemia cell line NT-1.

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Establishment and characterization of a rare atypical chronic myeloid leukemia cell line NT-1.

Leuk Res. 2014 Sep;38(9):1111-6

Authors: Qian J, Wang QR, Liu J, Jiang SH, Ni XQ, Lin ZH, Zhang YP, Liu H

Abstract

Human leukemia cell lines are of great value in leukemia research. In this study, we established and described the biological characteristics of a rare atypical chronic myeloid (aCML) leukemia cell line (NT-1). Mononuclear cells were isolated from the bone marrow of a patient with atypical chronic myeloid leukemia (Ph(-)/bcr(-)/abl(-)), and were passaged by liquid culture. Cells were maintained without any cytokines for over 1 year, and named NT-1. This cell line was extensively characterized using morphological assays, flow cytometry, cytogenetic analysis, clonogenic culture, quantitative fluorescent PCR, short tandem repeating sequence PCR (STR-PCR) and array-CGH. Its tumorigenic capacity was also examined in nude mice. The NT-1 cell line had morphological features of chronic myeloid leukemia and major myeloid markers (CD13, CD33, CD11b). Additionally, NT-1 expressed progenitor cells and natural killer cell-related antigens such as CD34, CD117, CD56. Cytogenetic analysis initially demonstrated two abnormalities: 47, xx, +8 and 47, xx, +8 accompanied by t(5;12)(q31;p13) translocation. The one-year passage process did not alter the karyotype. NT-1 cells maintained the same morphology, immunophenotyping and cytogenetic features as primary leukemia cells, which was strongly supported by STR-PCR results. Neither Epstein-Barr virus nor mycoplasma was detected in the NT-1 line. In addition, NT-1 cells showed high tumorigenic capacity in nude mice. NT-1 is a new atypical chronic myeloid leukemia cell line with the +8 and t(5,12) translocation, and exhibits high tumorigenicity in nude mice. This new cell line provides a useful tool for the study of leukemogenesis.

PMID: 25012564 [PubMed - indexed for MEDLINE]

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Managing children with chronic myeloid leukaemia (CML): recommendations for the management of CML in children and young people up to the age of 18 years.

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Managing children with chronic myeloid leukaemia (CML): recommendations for the management of CML in children and young people up to the age of 18 years.

Br J Haematol. 2014 Oct;167(1):33-47

Authors: de la Fuente J, Baruchel A, Biondi A, de Bont E, Dresse MF, Suttorp M, Millot F, International BFM Group (iBFM) Study Group Chronic Myeloid Leukaemia Committee

Abstract

Chronic myeloid leukaemia in children and young people is a relatively rare form of leukaemia that shows increased incidence with age and some evidence suggests that the molecular basis differs from that in adults. Significant advances in targeted therapy with the development and use in children of tyrosine kinase inhibitors and the ability to monitor and understand the prognostic significance of minimal residual disease by standardized molecular techniques has shifted the management of this condition from bone marrow transplantation as the main therapeutic modality to individualized treatment for each patient based on achieving specific milestones. The physiological changes occurring during childhood, particularly those affecting growth and development and the long-term use of treatment, pose specific challenges in this age group, which we are only beginning to understand.

PMID: 24976289 [PubMed - indexed for MEDLINE]

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Massive splenic infarction and portal vein thrombosis in children with chronic myeloid leukemia.

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Massive splenic infarction and portal vein thrombosis in children with chronic myeloid leukemia.

J Pediatr Hematol Oncol. 2014 Oct;36(7):e471-2

Authors: Aksu T, Erdem AY, Fettah A, Kaçar D, Avci Z, Yarali N, Tunc B

Abstract

Massive splenic infarction and portal vein thrombosis (PVT) due to chronic myeloid leukemia (CML) is extremely rare. We describe 2 children who were presented with massive splenic infarction and PVT in the course of CML. Massive splenic infarction and PVT treated with splenectomy in one and with medical treatment in another in whom PVT resolved by cytoreductive treatment, led to downsizing of spleen or splenectomy. Splenic infarct and PVT should be considered in CML patients with long-lasting severe abdominal pain despite appropriate medical attempts. Splenectomy should be spared for persistent symptoms and complications.

PMID: 24942025 [PubMed - indexed for MEDLINE]

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Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline.

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Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline.

Blood. 2014 Jul 24;124(4):511-8

Authors: Branford S, Yeung DT, Parker WT, Roberts ND, Purins L, Braley JA, Altamura HK, Yeoman AL, Georgievski J, Jamison BA, Phillis S, Donaldson Z, Leong M, Fletcher L, Seymour JF, Grigg AP, Ross DM, Hughes TP

Abstract

In chronic myeloid leukemia (CML) patients, a breakpoint cluster region-Abelson (BCR-ABL1) value >10% at 3 months of therapy is statistically associated with poorer outcome, yet many of these patients still achieve satisfactory outcomes. We investigated 528 first-line imatinib-treated patients to determine whether patients with the poorest outcome can be better discriminated at 3 months. All outcomes were significantly superior for the 410 patients with BCR-ABL1 ?10% at 3 months (P < .001). However, the poorest outcomes among the 95 evaluable patients with BCR-ABL1 >10% at 3 months were identified by the rate of BCR-ABL1 decline from baseline, assessed by estimating the number of days over which BCR-ABL1 halved. Patients with BCR-ABL1 halving time <76 days (n = 74) had significantly superior outcomes compared with patients whose BCR-ABL1 values did not halve by 76 days (n = 21; 4-year overall survival, 95% vs 58%, P = .0002; progression-free survival, 92% vs 63%, P = .008; failure-free survival, 59% vs 6%, P < .0001; and major molecular response, 54% vs 5%, P = .008). By multivariate analysis, the halving time was an independent predictor of outcome in this poor risk group. Our study highlighted that the rate of BCR-ABL1 decline may be a critical prognostic discriminator of the patients with very poor outcome among those >10% at 3 months. The International Randomized IFN vs STI571 (IRIS) trial was registered at http://www.clinicaltrials.gov as #NCT00006343. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was registered at http://www.clinicaltrials.gov as #NCT00124748. The Therapeutic Intensification in DE-novo Leukaemia (TIDEL) I trial was registered at http://www.ANZCTR.org.au as #ACTRN12607000614493. The TIDEL II trial was registered at http://www.ANZCTR.org.au as #ACTRN12607000325404.

PMID: 24859364 [PubMed - indexed for MEDLINE]

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Low level of TERC gene amplification between chronic myeloid leukaemia patients resistant and respond to imatinib mesylate treatment.

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Low level of TERC gene amplification between chronic myeloid leukaemia patients resistant and respond to imatinib mesylate treatment.

Asian Pac J Cancer Prev. 2014;15(4):1863-9

Authors: Mohamad Ashari ZS, Sulong S, Hassan R, Husin A, Sim GA, Abdul Wahid SF

Abstract

The amplification of telomerase component (TERC) gene could play an important role in generation and treatment of haematological malignancies. This present study was aimed to investigate copy number amplification status of TERC gene in chronic myeloid leukaemia (CML) patients who were being treated with imatinib mesylate (IM). Genomic DNA was extracted from peripheral blood of CML-IM Resistant (n=63), CML-IM Respond (n=63) and healthy individuals (n=30). TERC gene copy number predicted (CNP) and copy number calculated (CNC) were determined based on Taqman® Copy Number Assay. Fluorescence in situ hybridization (FISH) analysis was performed to confirm the normal signal pattern in C4 (calibrator) for TERC gene. Nine of CML patients showed TERC gene amplification (CNP=3), others had 2 CNP. A total of 17 CML patients expressed CNC>2.31 and the rest had 2.31>CNC>1.5. TERC gene CNP value in healthy individuals was 2 and their CNC value showed in range 1.59-2.31. The average CNC TERC gene copy number was 2.07, 1.99 and 1.94 in CML- IM Resistant patients, CML-IM Respond and healthy groups, respectively. No significant difference of TERC gene amplification observed between CML-IM Resistant and CML-IM Respond patients. Low levels of TERC gene amplification might not have a huge impact in haematological disorders especially in terms of resistance towards IM treatment.

PMID: 24641422 [PubMed - indexed for MEDLINE]

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Advanced sclerosis of the chest wall skin secondary to chronic graft-versus-host disease: a case with severe restrictive lung defect.

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Advanced sclerosis of the chest wall skin secondary to chronic graft-versus-host disease: a case with severe restrictive lung defect.

J Pediatr Hematol Oncol. 2014 Oct;36(7):e473-5

Authors: Ödek Ç, Kendirli T, ?leri T, Yaman A, Fatih Çakmakli H, Ince E, ?nce E, Ertem M

Abstract

Pulmonary chronic graft-versus-host disease (cGvHD) is one of the most common causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). Herein, we describe a patient with severe restrictive lung defect secondary to cGvHD. A 21-year-old male patient was admitted to our pediatric intensive care unit (PICU) with pneumonia and respiratory distress. He had a history of aHSCT for chronic myelogeneous leukemia at the age of 17 years. Six months after undergoing aHSCT, he had developed cGvHD involving skin, mouth, eye, lung, liver, and gastrointestinal tract. At the time of PICU admission he had respiratory distress and required ventilation support. Thorax high-resolution computed tomography was consistent with bronchiolitis obliterans. Although bronchiolitis obliterans is an obstructive lung defect, a restrictive pattern became prominent in the clinical course because of the sclerotic chest wall skin. The activity of cGvHD kept increasing despite the therapy and we lost the patient because of severe respiratory distress and massive hemoptysis secondary to bronchiectasis. In conclusion, pulmonary cGvHD can present with restrictive changes related with the advanced sclerosis of the chest wall skin. Performing a fasciotomy or a scar revision for the rigid chest wall in selected patients may improve the patients ventilation.

PMID: 24577553 [PubMed - indexed for MEDLINE]

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Primary distal femur T-cell lymphoma after allogeneic haematopoietic stem cell transplantation for chronic myeloid leukaemia: a rare case report and literature review.

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Primary distal femur T-cell lymphoma after allogeneic haematopoietic stem cell transplantation for chronic myeloid leukaemia: a rare case report and literature review.

J Int Med Res. 2014 Apr;42(2):598-605

Authors: Han Q, Sun M, Wu L, Chen J, Wang W, Liu C, Chen H, Du G

Abstract

Post-transplant lymphoproliferative disorders originating from T lymphocytes are a rare complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) that are not usually associated with Epstein-Barr virus infection. A male patient diagnosed at the age of 15 years with chronic myeloid leukaemia (in the chronic phase) was initially treated with oral hydroxyurea. The disease entered an accelerated phase when the patient was 22 years old. Complete remission was achieved after one course of homoharringtonine and cytarabine. The patient then underwent human leucocyte antigen-matched sibling donor allo-HSCT. Just over 6.5 years after the allo-HSCT, a second primary tumour was located in the distal femur and diagnosed as T-cell non-Hodgkin’s lymphoma (stage IV, group B). This was treated with various chemotherapy and radiotherapy regimens, but the outcomes were poor and the disease progressed. The T-cell lymphoma invaded many sites, including the skeleton, spleen and skin, and the patient died within 8 months of the diagnosis. This current case report highlights the need for the early detection and prevention of subsequent primary malignancies after allo-HSCT.

PMID: 24501166 [PubMed - indexed for MEDLINE]

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Pemphigus foliaceous-like reaction in a patient with chronic myeloid leukemia treated with the tyrosine kinase inhibitors nilotinib and dasatinib.

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Pemphigus foliaceous-like reaction in a patient with chronic myeloid leukemia treated with the tyrosine kinase inhibitors nilotinib and dasatinib.

Int J Dermatol. 2014 Apr;53(4):494-6

Authors: Nuno-Gonzalez A, Dehesa L, Ricotti C, Kerdel F

PMID: 24262013 [PubMed - indexed for MEDLINE]

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Initial presentation of acute myelogenous leukemia in the infiltrate underlying an actinic keratosis.

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

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Initial presentation of acute myelogenous leukemia in the infiltrate underlying an actinic keratosis.

Indian Dermatol Online J. 2014 Oct;5(4):508-9

Authors: Blattner C, DeDonato A, Blochin E, Kazlouskaya V, Elston DM

Abstract

We report an 85-year-old female patient who presented with an erythematous keratotic lesion on her temple suspicious of squamous cell carcinoma. Histological evaluation revealed actinic keratosis, but the underlying atypical infiltrate contained atypical myeloid forms consistent with acute myelogenous leukemia (AML). Upon further questioning, it was determined that the patient had a history of myelodysplastic syndrome. Her skin biopsy provided the first evidence of progression to AML. This case serves as an important reminder of the role the dermatopathologist plays in identifying serious systemic disease.

PMID: 25396143 [PubMed]

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Development of mycosis fungoides after bone marrow transplantation for chronic myeloid leukaemia: transmission from an allogeneic donor.

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Development of mycosis fungoides after bone marrow transplantation for chronic myeloid leukaemia: transmission from an allogeneic donor.

Br J Dermatol. 2014 Feb;170(2):462-7

Authors: Fahy CM, Fortune A, Quinn F, McMenamin ME, Browne PV, Langabeer S, McCarron S, Hayden P, Marren P, Ni Chonghaile M, Irvine AD, Vandenberghe E, Barnes L

Abstract

We report on a patient who developed donor-derived cutaneous T-cell lymphoma (CTCL) 4 years after successful treatment of chronic myeloid leukaemia with an allogeneic bone marrow transplant. The patient developed an eczematous rash unresponsive to topical therapy and immunosuppression. When CTCL was diagnosed in the recipient, his sibling donor had been attending his local dermatology unit with a maculosquamous rash, which proved subsequently to be mycosis fungoides. An identical pattern of donor and recipient clonality assessment and T-cell receptor gene sequencing indicated that the CTCL was probably transmitted in the bone marrow harvest. This suggests that CTCL cells circulate in the marrow at an early subclinical stage in this disease. This is the second case of donor-derived CTCL reported to date.

PMID: 24116988 [PubMed - indexed for MEDLINE]

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DNA hypermethylation of cell cycle (p15 and p16) and apoptotic (p14, p53, DAPK and TMS1) genes in peripheral blood of leukemia patients.

Posted by rob on November 13, 2014 under Uncategorized | Comments are off for this article

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DNA hypermethylation of cell cycle (p15 and p16) and apoptotic (p14, p53, DAPK and TMS1) genes in peripheral blood of leukemia patients.

Asian Pac J Cancer Prev. 2014;15(1):75-84

Authors: Bodoor K, Haddad Y, Alkhateeb A, Al-Abbadi A, Dowairi M, Magableh A, Bsoul N, Ghabkari A

Abstract

Aberrant DNA methylation of tumor suppressor genes has been reported in all major types of leukemia with potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. However, most of the previous reports did not show the extent of concurrent methylation of multiple genes in the four leukemia types. Here, we analyzed six key genes (p14, p15, p16, p53, DAPK and TMS1) for DNA methylation using methylation specific PCR to analyze peripheral blood of 78 leukemia patients (24 CML, 25 CLL, 12 AML, and 17 ALL) and 24 healthy volunteers. In CML, methylation was detected for p15 (11%), p16 (9%), p53 (23%) and DAPK (23%), in CLL, p14 (25%), p15 (19%), p16 (12%), p53 (17%) and DAPK (36%), in AML, p14 (8%), p15 (45%), p53 (9%) and DAPK (17%) and in ALL, p15 (14%), p16 (8%), and p53 (8%). This study highlighted an essential role of DAPK methylation in chronic leukemia in contrast to p15 methylation in the acute cases, whereas TMS1 hypermethylation was absent in all cases. Furthermore, hypermethylation of multiple genes per patient was observed, with obvious selectiveness in the 9p21 chromosomal region genes (p14, p15 and p16). Interestingly, methylation of p15 increased the risk of methylation in p53, and vice versa, by five folds (p=0.03) indicating possible synergistic epigenetic disruption of different phases of the cell cycle or between the cell cycle and apoptosis. The investigation of multiple relationships between methylated genes might shed light on tumor specific inactivation of the cell cycle and apoptotic pathways.

PMID: 24528084 [PubMed - indexed for MEDLINE]

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Assessment of changes in membrane properties of platelets from patients with chronic myeloid leukaemia in different stages of the disease.

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Assessment of changes in membrane properties of platelets from patients with chronic myeloid leukaemia in different stages of the disease.

Blood Coagul Fibrinolysis. 2014 Mar;25(2):142-50

Authors: Popov VM, Vladareanu AM, Bumbea H, Kovacs E, Moisescu MG, Onisai M, Iordache MM, Savopol T

Abstract

Patients with chronic myeloproliferative leukemia (CML) have frequent haemorrhage and/or thrombosis in their medical history. The mechanisms of these major and life-threatening complications remain unclear. Membrane organization influences many of the unique cellular functions and is strongly correlated, among other factors, to the membrane lipid composition; it may be evaluated by following up the membrane fluidity and aggregation properties of the platelet. In this study, we evaluated the platelet aggregation, the expression of platelet surface receptors, the membrane fluidity (as evaluated by fluorescence anisotropy) and its correlation to reactive oxygen species (ROS) production, in patients with chronic myeloid leukaemia (CML). It was found that the patients in accelerated and blastic phase of CML present an altered platelet aggregation response to all reagents except for ristocetin as compared with chronic phase group, which shows only epinephrine-altered response. We also found that BCR/ABL transcript leads to higher levels of ROS in accelerated and blastic CML phases. Patients without molecular remission have lower platelet membrane fluidity. We obtained a positive correlation between ROS level and membrane fluorescence anisotropy changes. The CD41 expression was decreased in CML patients and P selectin expression was found to be higher in these patients than in healthy volunteers. Platelets of CML patients have altered aggregation parameters in accelerated and blastic phases, in which BCR/ABL transcript level is increased. The increased level of ROS in CML patients without molecular remission is associated with a decrease in fluidity of platelet membrane and expression of CD41/CD61 receptors. These findings may contribute to understanding the mechanism of the altered platelet response reported in CML patients.

PMID: 24346354 [PubMed - indexed for MEDLINE]

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