Posted by rob on January 31, 2011 under Uncategorized | 
A molecular and functional analysis of large granular lymphocyte expansions in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors.
Leuk Lymphoma. 2011 Jan 27;
Authors: Powers JJ, Dubovsky JA, Epling-Burnette PK, Moscinski L, Zhang L, Mustjoki S, Sotomayor EM, Pinilla-Ibarz JA
Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for chronic myelogenous leukemia (CML). Off-target kinase inhibition has been implicated in the appearance of unique adverse effects, such as colitis and pleural effusions. In addition, some patients present oligoclonal expansions of large granular lymphocytes (LGLs). We sought to further investigate this phenomenon in 64 patients treated with five different TKIs. Clonal expansions of cytotoxic T lymphocytes (CTLs) were identified in all TKI-treated patient groups, but only in dasatinib-treated patients were these expansions characterized as LGLs. Survival factors known to be important in LGL leukemia (interleukin-15 [IL-15] transpresentation, plasma platelet-derived growth factor [PDGF]-BB levels, nuclear factor-?B [NF-?B] and T-bet activation) were found to be associated with TKI-induced LGL expansions. Interestingly, patients with LGL expansions had increased cytotoxicity against non-transformed endothelial cells, which may play a role in observed autoimmune-like side effects. Our results indicate that patients with CML treated with TKIs can develop T cell expansions, which can in certain cases be related to some adverse effects.
PMID: 21271862 [PubMed - as supplied by publisher]
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The association between the copy-number variations of ZMAT4 and hematological malignancy.
Hematology. 2011 Jan;16(1):20-23
Authors: Wan J, Gao Y, Zhao X, Wu Q, Fu X, Shao Y, Yang H, Guan M, Yu B, Zhang W
<title/> Copy-number variations (CNVs) have been found in association with various types of diseases, including hematological malignancies. A recent array-based study implicated the presence of CNVs of ZMAT4 in the genome of acute myelogenous leukemia. In our study, we collected 617 bone marrow samples from multitypes of hematological malignancies as well as healthy controls. We found significant association between the CNVs of ZMAT4 and these hematological malignancies, including acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, and myelodysplastic syndrome. We also examined the expression of ZMAT4 mRNA in the samples with 1 or 2 copies of DNA, and observed a weak yet positive correlation between the relative expression level and gene dosage. In conclusion, the CNVs of ZMAT4 have the potential to serve as a diagnostic indicator, alone or in combination with other markers, for hematological malignancies.
PMID: 21269563 [PubMed - as supplied by publisher]
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WT1 and its transcriptional cofactor BASP1 redirect the differentiation pathway of an established blood cell line.
Biochem J. 2011 Jan 26;
Authors: Goodfellow S, Rebello M, Toska E, Zeef L, Rudd S, Medler K, Roberts S
The Wilms’ tumour suppressor WT1 is a transcriptional regulator that plays a central role in organogenesis, and is mutated or aberrantly expressed in several childhood and adult malignancies. We previously identified BASP1 as a WT1 cofactor that suppresses the transcriptional activation function of WT1. Here we have analysed the dynamic between WT1 and BASP1 in the regulation of gene expression in myelogenous leukemia K562 cells. Our findings reveals that BASP1 is a significant regulator of WT1 that is recruited to WT1-binding sites and suppresses WT1-mediated transcriptional activation at several WT1 target genes. We find that WT1 and BASP1 can divert the differentiation programme of K562 cells to a non-blood cell type following induction by the phorbol ester PMA. WT1 and BASP1 cooperate to induce the differentiation of K562 cells to a neuronal-like morphology that exhibits extensive arborization and the expression of several genes involved in neurite outgrowth and synapse formation. Functional analysis revealed the relevance of the transcriptional reprogramming and morphological changes, in that the cells elicited a response to the neurotransmitter ATP. Taken together, our results reveal that WT1 and BASP1 can divert the lineage potential of an established blood cell line towards a cell with neuronal characteristics.
PMID: 21269271 [PubMed - as supplied by publisher]
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BCR-ABL stimulates mutagenic homologous DNA double-strand break repair via the DNA-end-processing factor CtIP.
Carcinogenesis. 2011 Jan;32(1):27-34
Authors: Salles D, Mencalha AL, Ireno IC, Wiesmüller L, Abdelhay E
Expression of BCR-ABL oncoprotein in chronic myeloid leukemia (CML) promotes neoplastic transformation of hematopoietic stem cells through modulation of diverse pathways. CML is a multistep disease, which evolves as a chronic phase and progresses to blast crisis. This progression has been associated with the appearance and accumulation of new cytogenetic anomalies and mutations. The mechanisms underlying the genomic instability promoted by BCR-ABL remain obscure. Through comparative analysis of different DNA double-strand break (DSB) repair mechanisms as a function of the BCR-ABL status in human megakaryocytic and CML cell lines, we found that BCR-ABL upregulates error-prone DSB repair pathways [single-strand annealing (SSA) and non-homologous end joining] rather than the high-fidelity mechanism of homologous recombination. Intriguingly, expression analysis of DSB repair pathway choice determining factors revealed increased levels of the protein CtIP in BCR-ABL-positive cells, particularly in response to irradiation. Moreover, treatment with the BCR-ABL kinase inhibitor, Imatinib Mesylate, abolished CtIP accumulation. When we silenced CtIP expression in cells with functional BCR-ABL, SSA enhancement by BCR-ABL was completely abrogated. Importantly, we also provide evidence that BCR-ABL stimulates DSB end resection, which is mediated by CtIP. Briefly, BCR-ABL promotes mutagenic DSB repair with the DSB end-processing protein CtIP acting as the key mediator downstream of BCR-ABL.
PMID: 20974687 [PubMed - indexed for MEDLINE]
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Umbilical cord blood transplantation from unrelated donors in adult patients with chronic myeloid leukaemia.
Best Pract Res Clin Haematol. 2010 Jun;23(2):217-22
Authors: Sanz J, Sanz GF
Allogeneic haematopoietic stem cell transplantation (HSCT) remains an important treatment option for patients with chronic myeloid leukaemia (CML) failing tyrosine-kinase inhibitors or progressing to an advanced phase. In this setting, umbilical cord blood (UCB) could be used as an alternative stem cell source for patients in whom allogeneic HSCT is indicated and lack a human leucocyte antigen (HLA)-matched adult donor. However, very little information exists on the outcome after UCB transplantation (UCBT) of these patients. Early registry-based studies of patients undergoing UCBT suggested a particularly poor outcome for patients with CML. However, more recent reports with special focus on patients with CML have confirmed feasibility and efficacy of the procedure and identified variables influencing short- and long-term outcomes. Currently, UCBT should be considered as a potential curative alternative for CML patients requiring allogeneic HSCT but lacking an appropriate adult donor.
PMID: 20837333 [PubMed - indexed for MEDLINE]
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Conclusion:? These findings, when combined with the data on 35INS, support the concept that loss of the C?terminus of BCR?ABL1 is associated with significant resistance to kinase inhibitors; this mechanism appears to be a major source of resistance to kinase inhibitors. (Source: Clinical and Laboratory Haematology)
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Researchers at Peking University Institute of Hematology have just published the results of their study which compared outcomes of imatinib mesylate (Gleevec) versus allogeneic stem cell transplant for patients with chronic myelogenous leukemia (CML) in accelerated phase (AP)….Read Full Post (Source: About.com Lymphoma)
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Posted by rob on January 18, 2011 under Uncategorized |
The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors.
Blood. 2011 Jan 13;
Authors: Nelson EA, Walker SR, Weisberg E, Bar-Natan M, Barrett R, Gashin LB, Terrell S, Klitgaard JL, Santo L, Addorio MR, Ebert BL, Griffin JD, Frank DA
The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, though CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we utilized a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, though it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes, and induces cell cycle arrest and apoptosis in CML cell lines. Pimozide also selectively inhibits colony formation of CD34+ bone marrow cells from CML patients. Importantly, pimozide induces similar effects in the presence of the T315I BCR/ABL mutation that renders the kinase resistant to presently available inhibitors. Simultaneously inhibiting STAT5 with pimozide and the kinase inhibitors imatinib or nilotinib shows enhanced effects in inhibiting STAT5 phosphorylation and in inducing apoptosis. Thus, targeting STAT5 may be an effective strategy for the treatment of CML and other myeloproliferative diseases.
PMID: 21233313 [PubMed - as supplied by publisher]
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The hRAD54 gene is a key member of the RAD52 epistasis group involved in repair of double-strand breaks (DSB) by homologous recombination (HR). Thus, alterations of the normal function of these genes could generate genetic instability, shifting the normal process of the cell cycle, leading the cells to develop into cancer. In this work we analyzed exon 18 of the hRAD54 gene, which has been previously reported by our group to carry a silent polymorphism, 2290 C/T (Ala730Ala), associated to meningiomas. We performed a PCR-SSCP method to detect the polymorphism in 239 samples including leukemia and normal control population. The results revealed that the 2290 C/T polymorphism has frequencies of 0.1 for the leukemia and 0.1 for the control group. These frequencies show no statistical differenc…
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In this study, we show that amiloride modulates the alternative splicing of various cancer genes, including Bcl-x, HIPK3, and BCR/ABL, and that this effect is not mainly related to pH alteration, which is a known effect of the drug. Splice modulation involved various splicing factors, with the phosphorylation state of serine-arginine–rich (SR) proteins also altered during the splicing process. Pretreatment with okadaic acid to inhibit protein phosphatase PP1 reversed partially the phosphorylation levels of SR proteins and also the amiloride-modulated yields of Bcl-xs and HIPK3 U(-) isoforms. Genome-wide detection of alternative splicing further revealed that many other apoptotic genes were regulated by amiloride, including APAF-1, CRK, and SURVIVIN. Various proteins of the Bcl-2 fami…
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Posted by rob on January 14, 2011 under Uncategorized |
Amiloride Modulates Alternative Splicing in Leukemic Cells and Resensitizes Bcr-AblT315I Mutant Cells to Imatinib.
Cancer Res. 2011 Jan 11;
Authors: Chang WH, Liu TC, Yang WK, Lee CC, Lin YH, Chen TY, Chang JG
The antihypertensive drug amiloride is being considered as a tactic to improve cancer therapy including that for chronic myelogenous leukemia. In this study, we show that amiloride modulates the alternative splicing of various cancer genes, including Bcl-x, HIPK3, and BCR/ABL, and that this effect is not mainly related to pH alteration, which is a known effect of the drug. Splice modulation involved various splicing factors, with the phosphorylation state of serine-arginine-rich (SR) proteins also altered during the splicing process. Pretreatment with okadaic acid to inhibit protein phosphatase PP1 reversed partially the phosphorylation levels of SR proteins and also the amiloride-modulated yields of Bcl-x(s) and HIPK3 U(-) isoforms. Genome-wide detection of alternative splicing further revealed that many other apoptotic genes were regulated by amiloride, including APAF-1, CRK, and SURVIVIN. Various proteins of the Bcl-2 family and MAPK kinases were found to be involved in amiloride-induced apoptosis. Moreover, the effect of amiloride on mRNA levels of Bcl-x was demonstrated to translate to the protein levels. Cotreatment of K562 and BaF3/Bcr-AblT315I cells with amiloride and imatinib induced more loss of cell viability than either agent alone. Our findings suggest that amiloride may offer a potential treatment option for chronic myelogenous leukemia either alone or in combination with imatinib. Cancer Res; 71(2); 383-92. ©2011 AACR.
PMID: 21224352 [PubMed - as supplied by publisher]
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[A comparative study of different intervention regimens for chronic myelogenous leukemia post allogeneic hematopoietic stem cell transplantation.]
Zhonghua Xue Ye Xue Za Zhi. 2010 Nov;31(11):758-762
Authors: Xu LP, Liu DH, Liu KY, Chen H, Han W, Zhang XH, Chen YH, Wang Y, Qin YZ, Huang XJ
OBJECTIVE: To study the efficacy and safety of immunotherapy and imatinib mesylate used in early post allogeneic hematopoietic stem cell transplantation (HSCT) for intervention. METHODS: Sixty-four chronic myelogenous leukemia (CML) patients received HSCT were analyzed retrospectively based on bcr-abl kinetics post HSCT. Patients were divided into three groups, imatinib group (n = 13), immunotherapy group (n = 20)and combining both group (n = 31). The primary endpoint is molecular response, the second endpoint is side effect related to intervention. RESULTS: There was no difference among the three groups in converting to bcr-abl negativity (86.0%, 90.0% and 83.9%, respectively, P = 0.126), 4 years cumulative relapse incidence (32.3%, 0% and 16.1%, respectively, P = 0.130) and 4 years OS (90.0%, 89.7%, 83.0%, respectively, P = 0.696). There was a trend of more relapse in Imatinib group than in immunotherapy group (P = 0.052). There were more hematological toxicity in imatinib and combining groups than that in immunotherapy group (30.8%, 38.7%, and 5.0%, respectively, P = 0.001). There was significant difference in the incidence of GVHD among the three groups (P = 0.000), being 95.0%, 0% and 67.7% in immunotherapy, imatinib and combining groups, respectively. Intervention related death occurred in 2 cases, both with discontinuation of CsA, graft failure in another patient with CsA withdrawal. No intervention related death occurred in the other two groups. CONCLUSIONS: All three regimens can give a quick and durable molecular remission in most of the patients, but side effects are different. The choice of regimen should be balanced with toxicity individually. CsA withdrawal is not the best choice for very early intervention, the long-term effect for patients received imatinib alone without GVHD is needed to be studied.
PMID: 21223731 [PubMed - as supplied by publisher]
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[Effect of astragalus polysaccharide on the function and maturation of plasmacytoid dendritic cells from chronic myelogenous leukemia before and after treatment.]
Zhonghua Xue Ye Xue Za Zhi. 2010 Nov;31(11):740-743
Authors: Liu LM, Zhang LS
OBJECTIVE: To explore the effect of astragalus polysaccharide (APS) on the function and maturation of chronic myelogenous leukemia (CML) peripheral blood mononuclear cells (PBMC)-derived plasmacytoid dendritic cells (pDCs). METHODS: CML-derived pDCs were sorted by flow cytometry, and then incubated with APS (at 0, 50, 100 and 200 mg/L). After 24 hours, the concentrations of IFN-?, IL-6, TNF-? were detected with ELISA. Five days later, the cultured cells were collected and analyzed for immotype, morphology and ultramicrostructure. RESULTS: The level of IFN-?, IL-6, TNF-? was significantly higher in samples from CML remission group than that in untreated pDCs, and newly diagnosed pDC (P < 0.05) or untreated group. APS could promote more pDCs differentiating to dendritic cells (DCs) in CML remission group than in untreated-pDCs in a dose-dependant manner (P < 0.05). CONCLUSION: APS can enhance the immune function of pDCs, promote differentiation and maturation of pDCs from CML patients.
PMID: 21223727 [PubMed - as supplied by publisher]
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