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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
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]
More
Posted by rob on under Uncategorized |
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)
More
Posted by rob on under Uncategorized |
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)
More
