What does a deep molecular response signify?

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What does a deep molecular response signify?

J Clin Oncol. 2014 Feb 10;32(5):471-4

Authors: Politi J, Shah NP

PMID: 24297955 [PubMed - indexed for MEDLINE]

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Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV.

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Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV.

J Clin Oncol. 2014 Feb 10;32(5):415-23

Authors: Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A

Abstract

PURPOSE: Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival.

PATIENTS AND METHODS: Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ? 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival.

RESULTS: Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression.

CONCLUSION: MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.

PMID: 24297946 [PubMed - indexed for MEDLINE]

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Translational Regulation of GPx-1 and GPx-4 by the mTOR Pathway.

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Translational Regulation of GPx-1 and GPx-4 by the mTOR Pathway.

PLoS One. 2014;9(4):e93472

Authors: Reinke EN, Ekoue DN, Bera S, Mahmud N, Diamond AM

Abstract

Glutathione peroxidase activity was previously determined to be elevated in lymphocytes obtained from patients treated with the Bcr-Abl kinase inhibitor imatinib mesylate. In order to expand upon this observation, the established chronic myelogenous leukemia cell lines KU812 and MEG-01 were treated with imatinib and the effect on several anti-oxidant proteins was determined. The levels of GPx-1 were significantly increased following treatment with imatinib. This increase was not due to altered steady-state mRNA levels, and appeared to be dependent on the expression of Bcr-Abl, as no increases were observed following imatinib treatment of cells that did not express the fusion protein. The nutrient-sensing signaling protein, mammalian target of rapamycin (mTOR), can be activated by Bcr-Abl and its activity regulates the translation of many different proteins. Treatment of those same cells used in the imatinib studies with rapamycin, an inhibitor of mTOR, resulted in elevated GPx-1 and GPx-4 protein levels independent of Bcr-Abl expression. These proteins all belong to the selenoprotein family of peptides that contain the UGA-encoded amino acid selenocysteine. Collectively, these data provide evidence of a novel means of regulating anti-oxidants of the selenoprotein family via the mTOR pathway.

PMID: 24691473 [PubMed - in process]

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A comparative study of Hasford score and Sokal index in prognostication of the novo chronic myeloid leukemia patients and a search for new prognostic markers.

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A comparative study of Hasford score and Sokal index in prognostication of the novo chronic myeloid leukemia patients and a search for new prognostic markers.

Indian J Pathol Microbiol. 2013 Jul-Sep;56(3):216-20

Authors: Sinha SK, Sinha S, Mandal PK, Bhattacharyya NK, Pandey A, Gupta P

Abstract

INTRODUCTION: Chronic myeloid leukemia (CML) is a common myeloproliferative disorder. Based on clinical and hematological parameters, two prognostic scoring systems, i.e., Hasford and Sokal index scoring systems are available to predict survival duration of CML patients on imatinib therapy.

AIMS AND OBJECTIVES: Our study’s objective is to compare Hasford score with Sokal index for the prognostication of de novo CML patients on therapy and find out new prognostic markers.

MATERIALS AND METHODS: This is a retrospective study. The study population comprised 66 patients who were followed up for 60 months. For each patient, at presentation, scoring was performed as per Hasford and Sokal index and Philadelphia chromosome analysis was carried out by conventional cytogenetics. Thereafter, hematological parameters were assessed 3 monthly and conventional cytogenetics was done yearly.

RESULTS: Out of these 66 patients, the number of patients belonging to low, intermediate and high risk categories are 21, 33 and 12 respectively by Hasford score and 12, 32 and 22 respectively by Sokal index. Eight patients, who had been categorized into high risk group by Sokal index but intermediate risk group by Hasford score, have shown better survival possibility as monitored by hematological and cytogenetic parameters. Ten cases, categorized into intermediate risk group by Sokal index but low risk group by Hasford score, is doing well till date.

CONCLUSIONS: This study shows that Hasford score predicts survival of the patients better than Sokal index. However, multicentric study over a large population is needed to give the final verdict.

PMID: 24152497 [PubMed - indexed for MEDLINE]

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Phosphorylation of c-Cbl and p85 PI3K Driven by All-trans Retinoic Acid and CD38 Depends on Lyn Kinase Activity.

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Phosphorylation of c-Cbl and p85 PI3K Driven by All-trans Retinoic Acid and CD38 Depends on Lyn Kinase Activity.

Cell Signal. 2014 Mar 28;

Authors: Congleton J, Shen M, Macdonald R, Malavasi F, Yen A

Abstract

The leukocyte antigen CD38 is expressed after all-trans retinoic acid (ATRA) treatment in HL-60 myelogenous leukemia cells and promotes induced myeloid differentiation when overexpressed. We found that Vav1 and SLP-76 associate with CD38 in two cell lines, and that these proteins complex with Lyn, a Src family kinase (SFK) upregulated by ATRA. SFK inhibitors PP2 and dasatinib, which enhance ATRA-induced differentiation, were used to evaluate the involvement of Lyn kinase activity in CD38-driven signaling. Cells treated with ATRA for 48hours followed by one hour of PP2 incubation show SFK/Lyn kinase inhibition. We observed that Lyn inhibition blocked c-Cbl and p85/p55 PI3K phosphorylation driven by the anti-CD38 agonistic mAb IB4 in ATRA-treated HL-60 cells and untreated CD38+ transfectants. In contrast, cells cultured for 48hours following concurrent ATRA and PP2 treatment did not show Lyn inhibition, suggesting ATRA regulates the effects on Lyn. 48hours of co-treatment preserved CD38-stimulated c-Cbl and p85/p55 PI3K phosphorylation indicating Lyn kinase activity is necessary for these events. In contrast another SFK inhibitor (dasatinib) which blocks Lyn activity with ATRA co-treatment prevented ATRA-induced c-Cbl phosphorylation and crippled p85 PI3K phosphorylation, indicating Lyn kinase activity is important for ATRA-propelled events potentially regulated by CD38. We found that loss of Lyn activity coincided with a decrease in Vav1/Lyn/CD38 and SLP-76/Lyn/CD38 interaction, suggesting these molecules form a complex that regulates CD38 signaling. Lyn inhibition also reduced Lyn and CD38 binding to p85 PI3K, indicating CD38 facilitates a complex responsible for PI3K phosphorylation. Therefore, Lyn kinase activity is important for CD38-associated signaling that may drive ATRA-induced differentiation.

PMID: 24686085 [PubMed - as supplied by publisher]

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Rapamycin combined with celecoxib enhanced antitumor effects of mono treatment on chronic myelogenous leukemia cells through downregulating mTOR pathway.

Posted by rob on April 1, 2014 under Uncategorized | Comments are off for this article

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Rapamycin combined with celecoxib enhanced antitumor effects of mono treatment on chronic myelogenous leukemia cells through downregulating mTOR pathway.

Tumour Biol. 2014 Mar 30;

Authors: Li J, Xue L, Hao H, Li R, Luo J

Abstract

Chronic myelogenous leukemia is a neoplasm of myeloid progenitor cells. We recently found that rapamycin could induce G0/G1 phase arrest and apoptosis and inhibit proliferation of K562 cells through inhibiting mammalian target of rapamycin (mTOR) pathway. However, whether rapamycin has synergistic effects with other drugs in chronic myelogenous leukemia (CML) therapies remain unclear. Therefore, we examined the effect of rapamycin combined with celecoxib on K562 cells in vitro. The survival rates showed a significant decrease in rapamycin + celecoxib treatment group. The combination treatment also increased the G0/G1 phase cells as compared to rapamycin or celecoxib treatment alone (P?<?0.05), accompanied with the decreased population of S phase cells. Meanwhile, the rate of apoptosis was 15.87?±?2.21 % in rapamycin + celecoxib treatment group, significantly higher than that in mono treatment group (P?<?0.05). Western blot and reverse transcription PCR (RT-PCR) analysis showed that the expressions of mTOR, 4E-BP1, and p70S6K were all significantly decreased in K562 cells after rapamycin + celecoxib treatment (P?<?0.05). In conclusion, rapamycin combined with celecoxib could induce cell cycle arrest and apoptosis and decrease the expressions of mTOR, 4E-BP1, and p70S6K. It suggested that the combination could enhance the antitumor effects of mono treatment on CML cells through downregulating mTOR pathway.

PMID: 24682932 [PubMed - as supplied by publisher]

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Clofarabine in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin) in patients with previously untreated intermediate and bad-risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): phase I results of an ongoing phase I/II study of the leukemia groups of EORTC and GIMEMA (EORTC GIMEMA 06061/AML-14A trial).

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Clofarabine in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin) in patients with previously untreated intermediate and bad-risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): phase I results of an ongoing phase I/II study of the leukemia groups of EORTC and GIMEMA (EORTC GIMEMA 06061/AML-14A trial).

Ann Hematol. 2014 Mar 29;

Authors: Willemze R, Suciu S, Muus P, Halkes CJ, Meloni G, Meert L, Karrasch M, Rapion J, Vignetti M, Amadori S, de Witte T, Marie JP

Abstract

This study aims to determine the maximum tolerated dose (MTD) of clofarabine combined with the EORTC-GIMEMA 3?+?10 induction regimen (idarubicin?+?cytosine arabinoside) in adults with untreated acute myelogenous leukemia or high-risk myelodysplastic syndrome. In this phase I trial, 25 patients (median age 56 years) received 5 days of clofarabine as 1-h infusion (arm A) or push injection (arm B) at the dose level of 5?×?10 or 5?×?15 mg/m(2)/day in an algorithmic dose escalation 3?+?3 design. A consolidation course (intermediate dose cytosine arabinoside, idarubicin) was planned for patients in complete remission (CR). Primary endpoint was safety and tolerance as measured by dose limiting toxicity (DLT); secondary endpoints were response rate, other grade III/IV toxicities, and hematological recovery after induction and consolidation. Five DLTs were observed (in arm A: one DLT at 10 mg/m(2)/day, three at 15 mg/m(2)/day; in arm B: one DLT at 15 mg/m(2)/day). Three patients receiving 15 mg/m(2)/day were withdrawn due to adverse events not classified as DLT. Prolonged hypoplasia was observed in five patients. CR?+?complete remission with incomplete recovery were achieved in 21 patients (11/12 (92 %) receiving clofarabine 10 mg/m(2)/day; 10/13 (77 %) receiving clofarabine 15 mg/m(2)/day). Clofarabine, 5?×?10 mg/m(2)/day, resulted in one DLT and no early treatment withdrawals. MTD of clofarabine combined with cytosine arabinoside and idarubicin is 5?×?10 mg/m(2)/day.

PMID: 24682421 [PubMed - as supplied by publisher]

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Polycythemia vera developed after a major molecular response to imatinib mesylate treatment in a patient with chronic myelogenous leukemia.

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Polycythemia vera developed after a major molecular response to imatinib mesylate treatment in a patient with chronic myelogenous leukemia.

Rinsho Ketsueki. 2014;55(3):360-365

Authors: Jomen W, Kuroda H, Matsuno T, Sato M, Yamada M, Abe T, Sakurai T, Fujii S, Maeda M, Fujita M, Kato J, Nojiri S

Abstract

A 68-year-old man complained of dizziness and was referred to our hospital by his primary physician for evaluation of an elevated leukocyte count. In April 2002, soon after the chronic phase of chronic myeloid leukemia had been diagnosed, he was treated with imatinib. In March 2010, imatinib treatment was completed and the BCR/ABL fusion gene had become undetectable by real time quantitative PCR. Subsequently, leukocyte counts and the hematocrit gradually rose. In August 2012, a bone marrow aspirate showed hypercellular marrow with marked erythroid hyperplasia and the presence of the JAK2 gene V617F mutation. He was diagnosed with polycythemia vera. Phlebotomy and chemotherapy were started in addition to imatinib administration. Shortly thereafter complete blood counts returned to normal levels.

PMID: 24681942 [PubMed - as supplied by publisher]

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Immune reconstitution after allogeneic hematopoietic stem cell transplantation is associated with selective control of JC virus reactivation.

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Immune reconstitution after allogeneic hematopoietic stem cell transplantation is associated with selective control of JC virus reactivation.

Biol Blood Marrow Transplant. 2014 Mar 27;

Authors: Tan CS, Broge TA, Ngo L, Gheuens S, Viscidi R, Bord E, Rosenblatt J, Wong M, Avigan D, Koralnik IJ

Abstract

JCV causes progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. The mechanism of JCV reactivation and immunity in a transplanted immune system remains unclear. We prospectively studied 30 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT), and collected blood and urine samples pre-HSCT, 3, 6, and 12-18 months after HSCT. Pre-HSCT, JCV DNA was detected in 7/30 urine, 5/30 PBMC and 6/30 plasma samples. While JC viruria remained stable after HSCT with detection in 5/21 samples, viremia was detected in only 1/22 plasma and none of 22 PBMC samples 12-18 months after HSCT. Prevalence of anti-JCV IgG was 83% pre-HSCT and decreased to 72% at 12-18 months. Anti-JCV IgM was rarely detected. JCV-specific CD4(+) and CD8(+) T cell responses increased 12-18 months after HSCT. While JC viruria correlated directly with detection of anti-JCV IgG, the cellular immune response to JCV measured by ELISpot was inversely correlated with anti-JCV IgG response. The diagnosis of acute myelogenous leukemia and age groups were two independent patient factors associated with significantly reduced cellular immune responses to JCV. This prospective study in HSCT patients provides a model of interactions between the host immune response and viral activation in multiple compartments during the recovery of the immune system.

PMID: 24680976 [PubMed - as supplied by publisher]

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[Tyrosine kinase inhibitors (TKI): a new revolution in the treatment of chronic myeloid leukemia (CML)].

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[Tyrosine kinase inhibitors (TKI): a new revolution in the treatment of chronic myeloid leukemia (CML)].

Gac Med Mex. 2013 Nov-Dec;149(6):646-54

Authors: Avilés-Vázquez S, Chávez-González A, Mayani H

Abstract

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia associated with the t(9,22)(q34:q11) reciprocal translocation, also known as Philadelphia chromosome (Ph). As a result of such abnormality, a chimeric gene (bcr-abl) is produced that is translated into a chimeric protein (BCR-ABL), a constitutively activated tyrosine kinase. Major cell dysfunctions result from this abnormal kinase activity, including increased proliferation and reduced apoptosis. Based on the structure of BCR-ABL, several molecules have been designed that inhibit its kinase activity. Five such molecules have already been brought into the clinic for the treatment of Ph+ CML patients. Good results have been obtained in terms of patients’ remission rates and quality of life. Some major problems, however, have been observed. Firstly, a significant proportion of patients develop resistance to the drugs; secondly, it is clear that such drugs affect most of the leukemic cells, but do not eliminate leukemia stem cells. Thus, important CML-related challenges remain to be solved in the near future.

PMID: 24276188 [PubMed - indexed for MEDLINE]

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STAT pathway in the regulation of zoledronic acid-induced apoptosis in chronic myeloid leukemia cells.

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STAT pathway in the regulation of zoledronic acid-induced apoptosis in chronic myeloid leukemia cells.

Biomed Pharmacother. 2013 Jul;67(6):527-32

Authors: Kiper HD, Tezcanli Kaymaz B, Gokbulut AA, Selvi N, Avci CB, Kosova B, Iskender G, Yandim MK, Gunduz C, Sahin F, Baran Y, Saydam G

Abstract

In this study, we aimed to evaluate the cytotoxic and apoptotic effects of zoledronic acid on K562 chronic myeloid leukemia (CML) cells and to examine the roles of STAT genes on zoledronic acid-induced apoptosis. The results showed that zoledronic acid decreased proliferation, and induced apoptosis in K562 cells in a dose- and time-dependent manner. mRNA and protein levels of STAT3, -5A and -5B genes were significantly reduced in zoledronic acid-treated K562 cells. These data indicated that STAT inhibition by zoledronic acid may be therapeutic in CML patients following the confirmation with clinical studies.

PMID: 23725755 [PubMed - indexed for MEDLINE]

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A significant proportion of patients with chronic myeloid leukemia and suboptimal response according to European Leukemia Net criteria have excellent prognosis without treatment change.

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A significant proportion of patients with chronic myeloid leukemia and suboptimal response according to European Leukemia Net criteria have excellent prognosis without treatment change.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2013 Jun;157(2):181-8

Authors: Rohon P, Faber E, Divoka M, Rozmanova S, Friedecky D, Jarosova M, Indrak K

Abstract

BACKGROUND: The Recommendations of the European Leukemia Net (ELN) have become an essential tool in the management and prognosis of patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). However, the definition of suboptimal response remains under discussion.

METHODS: We used conventional cytogenetics for the detection of clonal changes in Ph-positive and negative clones. RT-PCR and sequencing were carried out on peripheral blood leukocytes to detect the type of BCR-ABL1 transcript. The BCR-ABL1 mutational status was assessed using sequencing of RT-PCR products. High performance capillary electrophoresis for determination of imatinib (IMA) plasma concentration was used.

RESULTS: A retrospective study of 110 patients diagnosed with chronic-phase (CP) CML treated with IMA or 2(nd) generation TKIs in the years 2000-2009 focused on analysis of patients with suboptimal response according to ELN criteria. 40 patients were administered IMA as first-line therapy and 70 had been pretreated with interferon-alpha (IFN-?) with or without Ara-C and/or hydroxyurea (HU) for a median 12 months (range, 1-92 months). After adjusting for the ELN criteria, major molecular response (MMR) was achieved after median 34 and 39 months in 66.7% and 41.7% of patients after the first and second-line IMA therapy with suboptimal response defined as lack of achievement of MMR at the 18(th) month of treatment, respectively. In comparison to patients with optimal response, patients with suboptimal response did not show significant differences in overall survival (OS) or progression-free survival (PFS). Cytogenetic assays demonstrated additional chromosome abnormalities (ACAs): chromosome 8 trisomy in a Ph-negative clone during the IMA treatment (in 1 case) and der(9q) in Ph-positive clone (in 2 cases); in patients receiving first-line IMA only chromosome 8 trisomy was observed which was associated with myelodysplastic syndrome – this was the only case where hematopoietic stem cell transplantation (HSCT) was performed. During the treatment with IMA in both subgroups no regulatory mutations in the ABL kinase domain were confirmed.

CONCLUSION: We believe that the category of suboptimal response should be redefined or withdrawn from the ELN 2009 recommendations for management of CML patients treated with TKIs. Patients with suboptimal response who have no additional risks (additional cytogenetic abnormalities or BCR-ABL1 regulatory mutations) may remain on IMA treatment while patients with these risks should be switched to the 2(nd) generation TKIs.

PMID: 22660209 [PubMed - indexed for MEDLINE]

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Isolation of Mycobacterium branderi, an unusual species from an acute myelogenous leukemia patient.

Posted by rob on March 29, 2014 under Uncategorized | Comments are off for this article

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Isolation of Mycobacterium branderi, an unusual species from an acute myelogenous leukemia patient.

Avicenna J Med. 2014 Jan;4(1):17-9

Authors: Marjani M, Farshidpour M, Tabarsi P, Sheikholslami FM, Farnia P

Abstract

We report a case of pulmonary infection caused by Mycobacterium branderi, a slow growing non-tuberculosis mycobacteria, in a patient with acute myelogenous leukemia. The pulmonary disease was treated successfully with the combination of Ciprofloxacin, Doxycycline and Clarithromycin. M. branderi may be considered as an opportunistic pathogen, especially among immunologically compromised patients.

PMID: 24678467 [PubMed]

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Lineage-specific function of Engrailed-2 in the progression of chronic myelogenous leukemia to T-cell blast crisis.

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Lineage-specific function of Engrailed-2 in the progression of chronic myelogenous leukemia to T-cell blast crisis.

Cell Cycle. 2014 Mar 25;13(11)

Authors: Abollo-Jiménez F, Campos-Sánchez E, Toboso-Navasa A, Vicente-Dueñas C, González-Herrero I, Alonso-Escudero E, González M, Segura V, Blanco O, Martínez-Climent JA, Sánchez-García I, Cobaleda C

Abstract

In hematopoietic malignancies, oncogenic alterations interfere with cellular differentiation and lead to tumoral development. Identification of the proteins regulating differentiation is essential to understand how they are altered in malignancies. Chronic myelogenous leukemia (CML) is a biphasic disease initiated by an alteration taking place in hematopoietic stem cells. CML progresses to a blast crisis (BC) due to a secondary differentiation block in any of the hematopoietic lineages. However, the molecular mechanisms of CML evolution to T-cell BC remain unclear. Here, we have profiled the changes in DNA methylation patterns in human samples from BC-CML, in order to identify genes whose expression is epigenetically silenced during progression to T-cell lineage-specific BC. We have found that the CpG-island of the ENGRAILED-2 (EN2) gene becomes methylated in this progression. Afterwards, we demonstrate that En2 is expressed during T-cell development in mice and humans. Finally, we further show that genetic deletion of En2 in a CML transgenic mouse model induces a T-cell lineage BC that recapitulates human disease. These results identify En2 as a new regulator of T-cell differentiation whose disruption induces a malignant T-cell fate in CML progression, and validate the strategy used to identify new developmental regulators of hematopoiesis.

PMID: 24675889 [PubMed - as supplied by publisher]

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Preclinical characterization of AMG 330, a CD3/CD33-bispecific T-cell-engaging antibody with potential for treatment of acute myelogenous leukemia.

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Preclinical characterization of AMG 330, a CD3/CD33-bispecific T-cell-engaging antibody with potential for treatment of acute myelogenous leukemia.

Mol Cancer Ther. 2014 Mar 27;

Authors: Friedrich M, Henn A, Raum T, Bajtus M, Matthes K, Hendrich L, Wahl J, Hoffmann P, Kischel R, Kvesic M, Sloostra JW, Baeuerle PA, Kufer P, Rattel B

Abstract

There is high demand for novel therapeutic options for patients with acute myelogenous leukemia (AML). One possible approach is the bispecific T-cell engaging (BiTE®) antibody AMG 330 with dual specificity for CD3 and the sialic acid-binding lectin CD33 (SIGLEC-3), which is frequently expressed on the surface of AML blasts and leukemic stem cells. AMG 330 binds with low nanomolar affinity to CD33 and CD3? of both human and cynomolgus monkey origin. Eleven human AML cell lines expressing between 14,400 and 56,700 CD33 molecules per cell were all potently lysed with EC50 values ranging between 0.4 and 3 pM (18-149 pg/mL) by previously resting, AMG 330-redirected T-cells. Complete lysis was achieved after 40 hours of incubation. In the presence of AML cells, AMG 330 specifically induced expression of CD69 and CD25 as well as release of interferon-?, TNF, IL-2, IL-10 and IL-6. Ex vivo, AMG 330 mediated autologous depletion of CD33-positive cells from cynomolgous monkey bone marrow aspirates. Soluble CD33 at concentrations found in bone marrow of AML patients did not significantly impact activities of AMG 330. Neoexpression of CD33 on newly activated T-cells was negligible as it was limited to 6% of T-cells in only three out of ten human donors tested. Daily intravenous administration with as low as 0.002 mg/kg AMG 330 significantly prolonged survival of immunodeficient mice adoptively transferred with human MOLM-13 AML cells and human T-cells. AMG 330 warrants further development as a potential therapy for AML.

PMID: 24674885 [PubMed - as supplied by publisher]

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Influence of CYP1A1, GST polymorphisms and susceptibility risk of chronic myeloid leukemia in Syrian population.

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Influence of CYP1A1, GST polymorphisms and susceptibility risk of chronic myeloid leukemia in Syrian population.

Med Oncol. 2014 May;31(5):889

Authors: Al-Achkar W, Azeiz G, Moassass F, Wafa A

Abstract

In the present study, we investigated the associations of polymorphisms in cytochrome P450 gene (CYP1A1), glutathione S-transferase genes (GSTM1 and GSTT1) with chronic myelogenous leukemia (CML). A total of 126 patients with CML and 172 healthy volunteers were genotyped, and the DNA was isolated from their blood samples. The polymorphisms were assessed by polymerase chain reaction (PCR) restriction fragment length polymorphism-based methods and multiplex PCR. Logistic regression analyses showed significant risk of CML associated with CYP1A1 Val allele [odds ratio (OR) 3.3, 95 % confidence intervals (CI) 1.96-5.53], (p < 0.0001) while CYP1A1 Val/Val homozygotes were observed only in the CML patients. There was statistically significant difference in the frequency of GSTM1 and GSTT1 null genotypes. The GSTT1-null genotype was slightly higher in 27 % of CML cases and 16.7 % of controls (OR 1.98, 95 % CI 1.12-3.5) (p < 0.020). The GSTM1 null was higher in 42.8 % of CML cases and 22.7 % of controls (OR 2.55, 95 % CI 1.54-4.22) (p < 0.00024). The individuals carrying CYP1A1 Ile/Val (AG) and GSTM1 null genotype have 9.9 times higher risk to be CML than those carrying CYP1A1 Ile/Ile (AA) and GSTM1 present genotype (OR 9.9, 95 % CI 2.7-36.3) (p < 0.0001). This suggests that the association of the GSTM1 null genotype, either alone or in combination with GSTT1 null, with CYP1AI heterozygous leads to the CML risk.

PMID: 24671854 [PubMed - in process]

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Bone marrow microenvironment confers imatinib resistance to chronic myelogenous leukemia and oroxylin A reverses the resistance by suppressing Stat3 pathway.

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Bone marrow microenvironment confers imatinib resistance to chronic myelogenous leukemia and oroxylin A reverses the resistance by suppressing Stat3 pathway.

Arch Toxicol. 2014 Mar 27;

Authors: Li X, Miao H, Zhang Y, Li W, Li Z, Zhou Y, Zhao L, Guo Q

Abstract

Imatinib (IM) is highly effective in treatment of chronic myeloid leukemia (CML) but does not eliminate minimal residual disease (MRD), which remains a potential source of relapse. IM treatment effectively inhibits BCR-ABL kinase activity in CML cells, suggesting that additional kinase-independent mechanisms contribute to the presence of MRD. Bone marrow (BM) microenvironment protecting CML cells from IM treatment was investigated. Culturing CML cell line K562 in human stromal cell line HS-5-derived conditioned medium significantly inhibited apoptosis induced by IM, which was soluble factor-mediated drug resistance (SFM-DR). The BM stroma-derived soluble factors could enhance the resistance of K562 cells to IM by increasing Stat3 phosphorylation on tyrosine 705 and subsequently increasing the expression of anti-apoptotic proteins and P-glycoprotein (P-gp) in K562 cells. Furthermore, the reversal effect of oroxylin A, a naturally monoflavonoid isolated from the root of Scutellaria baicalensis Georgi, in K562 cells within the SFM-DR model was detected. After treatment of weakly toxic concentration of oroxylin A, the apoptosis of K562 cells induced by IM was increased dramatically through suppressing Stat3 pathway. In addition, the in vivo study showed that oroxylin A potentiates the inhibitory effects of IM on leukemia development by suppressing Stat3 pathway in the K562 xenograft model. In conclusion, IM-induced resistance in K562 cells within the SFM-DR model correlated with increasing Stat3 signaling and upregulating P-gp expression through Stat3 pathway. Additionally, oroxylin A improved the sensitivity of K562 cells to IM in SFM-DR model and in vivo, and the underlying mechanism attributed to the suppression of Stat3 pathway, which suggested oroxylin A might be a promising agent for treatment designed to eradicate MRD in CML patients.

PMID: 24671465 [PubMed - as supplied by publisher]

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Discovery of imatinib-responsive FIP1L1-PDGFRA mutation during refractory acute myeloid leukemia transformation of chronic myelomonocytic leukemia.

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Discovery of imatinib-responsive FIP1L1-PDGFRA mutation during refractory acute myeloid leukemia transformation of chronic myelomonocytic leukemia.

J Hematol Oncol. 2014 Mar 27;7(1):26

Authors: Shah S, Loghavi S, Garcia-Manero G, Khoury JD

Abstract

The FIP1L1-PDGFRA rearrangement results in constitutive activation of the tyrosine kinase PDGFRA. Neoplasms harboring this rearrangement are responsive to imatinib mesylate at doses much lower than those recommended for the treatment of chronic myelogenous leukemia. Only a single report has described the identification of FIP1L1-PDGFRA in chronic myelomonocytic leukemia (CMML). Herein, we present a case report of a patient in whom the FIP1L1-PDGFRA was discovered as he evolved from CMML to acute myeloid leukemia (AML). The presence of a dominant neoplastic clone with FIP1L1-PDGFRA rearrangement was suspected on the basis of sudden onset of peripheral and bone marrow eosinophilia and confirmed by fluorescence in situ hybridization and molecular diagnostic tests. Whereas the patient was initially refractory to chemotherapy before the rearrangement was detected, subsequent therapy with imatinib led to complete remission.

PMID: 24669761 [PubMed - as supplied by publisher]

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The European Medicines Agency Review of Bosutinib for the Treatment of Adult Patients With Chronic Myelogenous Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

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The European Medicines Agency Review of Bosutinib for the Treatment of Adult Patients With Chronic Myelogenous Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

Oncologist. 2014 Mar 25;

Authors: Hanaizi Z, Unkrig C, Enzmann H, Camarero J, Sancho-Lopez A, Salmonson T, Gisselbrecht C, Laane E, Pignatti F

Abstract

On March 27, 2013, a conditional marketing authorization valid throughout the European Union was issued for bosutinib (Bosulif) for the treatment of adult patients with chronic-phase, accelerated-phase, and blast-phase Philadelphia chromosome positive (Ph(+)) chronic myelogenous leukemia (CML) previously treated with one tyrosine kinase inhibitor or more and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Bosutinib is a kinase inhibitor that targets the BCR-ABL kinase. The recommended dose is 500 mg of bosutinib once daily. The main evidence of efficacy for bosutinib was based on a CML subgroup analysis of study 3160A4-200, a phase I/II study of bosutinib in Ph(+) leukemia in imatinib-resistant or intolerant CML. The subgroup was defined based on the presence of a BCR-ABL kinase domain mutation that would be expected to confer resistance to dasatinib (F317, E255) or nilotinib (E255, Y253, F359) and expected to have sensitivity to bosutinib or based on the presence of medical conditions or prior toxicities that may predispose the patient to unacceptable risk in the setting of nilotinib or dasatinib therapy. A conditional marketing authorization was granted because of the limited evidence of efficacy and safety currently supporting this last-line indication.

PMID: 24668331 [PubMed - as supplied by publisher]

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Multi-drug-resistant cells enriched from chronic myeloid leukemia cells by Doxorubicin possess tumor-initiating-cell properties.

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Multi-drug-resistant cells enriched from chronic myeloid leukemia cells by Doxorubicin possess tumor-initiating-cell properties.

J Pharmacol Sci. 2013;122(4):299-304

Authors: Xin H, Kong Y, Jiang X, Wang K, Qin X, Miao ZH, Zhu Y, Tan W

Abstract

Multiple drug resistance (MDR) occurring during chemotherapy is a major obstacle for treatment of cancers using chemotherapeutic drugs; thus, the mechanisms underlying MDR have attracted intensive attention. Many studies have shown that tumor-initiating cells exhibit a chemotherapeutic tolerance characteristic. However, whether the MDR cells possess tumor-initiating cells properties and its underlying mechanisms remain to be fully elucidated. In this study, we utilized a well-established MDR cell line K562/A02 enriched by doxorubicin from K562 cells to determine if the K562/A02 cells possess tumor-initiating properties and investigated its potential molecular mechanisms. We observed that the expressions of Oct4, Sox2, and Nanog, all of which are well-characterized stem cell markers, in K562/A02 cells were elevated in comparison to parental K562 cells; in addition, we found that K562/A02 cells exhibited more potent in vitro and in vivo tumor-initiating properties, as revealed by sphere assay, self-renewal assay, soft agar assay, and animal studies. Furthermore, our data suggest that snail and twist1, two well known transcriptional factors for the epithelial-mesenchymal transition (EMT) program, may be potentially involved in the acquisition of tumor-initiating properties of K562/A02 cells. Thus, our study demonstrates that MDR K562/A02 cells possess tumor-initiating properties, most likely due to the elevated expressions of snail and twist1.

PMID: 23903006 [PubMed - indexed for MEDLINE]

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