Posted by rob on March 31, 2010 under Uncategorized | 
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by unregulated overproduction of myeloid cells. Pulmonary involvement by myeloid leukemia is relatively uncommon and is seen mainly in patients with severe disease. The most common form of pulmonary involvement consists of leukemic infiltration along lymphatics in the peribronchovascular, septal and pleural interstitial tissue . (Source: Leukemia Research)
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In a recent report in this journal Hoshino et al. reported that JUNB was not a target for frequent promoter methylation in CML, either in chronic phase or in blast crisis. These results were in stark contrast to a previous report of Yang et al. which had suggested that hypermethylation of JUNB was widespread in CML patients and was a major mechanism for downregulation of JUNB in CML blast crisis. Thus the role of methylation in regulating JUNB in CML remains controversial. (Source: Leukemia Research)
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A summer of hematologic science. Highlights from the 45th Annual Meeting of the American Society of Clinical Oncology, the 14th Congress of the European Hematology Association, and the 2009 Pan Pacific Lymphoma Conference.
Clin Adv Hematol Oncol. 2009 Sep;7(9 Suppl 15):1-22; quiz 23-4
Authors: Cheson BD, Ashforth E
PMID: 20102012 [PubMed - indexed for MEDLINE]
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Successful prior treatment with dasatinib followed by stem cell transplantation in a patient with CML in blastic crisis with a BCR-ABL mutation.
Int J Hematol. 2010 Jan;91(1):128-31
Authors: Gotoh M, Tauchi T, Yoshizawa S, Kitahara T, Kiguchi T, Kimura Y, Ohyashiki K
We report a case of imatinib- and nilotinib-resistant Ph-positive chronic myeloid leukemia (CML) in blast crisis in which successful pretreatment with dasatinib with cord blood transplantation resulted in molecular remission. Before dasatinib therapy, the patient was found to have a F359V BCR-ABL mutation. He was treated with dasatinib for just 16, 19 days before allogeneic stem cell transplantation. This successful case indicates that reduction of tumor burden by second-generation tyrosine kinase inhibitors, in combination with stem cell transplantation, might be effective to treat CML, even in the advanced phase.
PMID: 20047099 [PubMed - indexed for MEDLINE]
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A man with concomitant polycythaemia vera and chronic myeloid leukemia: the dynamics of the two disorders.
Int J Hematol. 2010 Jan;91(1):136-9
Authors: Bee PC, Gan GG, Nadarajan VS, Latiff NA, Menaka N
The co-occurrence of JAK2 V617F mutation with BCR-ABL reciprocal translocation is uncommon. We report a 60-year-old man who initially presented with phenotype of polycythemia vera (PV), which evolved into chronic myeloid leukemia and back to PV once treatment with imatinib was commenced. JAK2 V617F mutation and BCR-ABL fusion transcripts were detected in the initial sample. However, JAK2 V617F alleles diminished when BCR-ABL mRNA burden increased and reappeared once the patient was commenced on imatinib. The dynamic interaction between JAK2 V617F and BCR-ABL implies that two independent clones exist with the JAK2 V617F clone only achieving clonal dominance when BCR-ABL positive clones are suppressed by imatinib.
PMID: 20047097 [PubMed - indexed for MEDLINE]
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Nilotinib-mediated inhibition of ABCB1 increases intracellular concentration of dasatinib in CML cells: implications for combination TKI therapy.
Leukemia. 2010 Mar;24(3):658-60
Authors: Hiwase DK, White D, Zrim S, Saunders V, Melo JV, Hughes TP
PMID: 20010623 [PubMed - indexed for MEDLINE]
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Similar patterns of chromosome abnormalities in CML occur in addition to the Philadelphia chromosome with or without tyrosine kinase inhibitor treatment.
Leukemia. 2010 Mar;24(3):638-40
Authors: Haferlach C, Bacher U, Schnittger S, Weiss T, Kern W, Haferlach T
PMID: 19865111 [PubMed - indexed for MEDLINE]
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A peptide biosensor for detecting intracellular Abl kinase activity using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Anal Biochem. 2010 Feb 1;397(1):73-8
Authors: Placzek EA, Plebanek MP, Lipchik AM, Kidd SR, Parker LL
Many cancers are characterized by changes in protein phosphorylation as a result of kinase dysregulation. Disruption of Abl kinase signaling through the Philadelphia chromosome (causing the Bcr-Abl mutation) in chronic myeloid leukemia (CML) has provided a paradigm for development of kinase inhibitor drugs such as the specific inhibitor imatinib (also known as STI571 or Gleevec). However, because patients are treated indefinitely with this drug to maintain remission, resistance is increasingly becoming an issue. Although there are many ways to detect kinase activity, most lack the ability to “multiplex” the analysis (i.e., to detect more than one substrate simultaneously). Here we report a novel biosensor for detecting Abl kinase activity and sensitivity to inhibitor in live intact cells overexpressing a CML model Abl kinase construct. This straightforward methodology could eventually provide a new tool for detecting kinase activity and inhibitor drug response in cancer cells that overexpress oncogenic kinases.
PMID: 19818327 [PubMed - indexed for MEDLINE]
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Posted by rob on March 28, 2010 under Uncategorized |
A V530I Mutation in c-KIT Exon 10 Is Associated to Imatinib Response in Extraabdominal Aggressive Fibromatosis.
Sarcoma. 2010;2010:458156
Authors: Kurtz JE, Asmane I, Voegeli AC, Neuville A, Dufresne A, Litique V, Chevreau C, Bergerat JP
Aggressive fibromatosis (AF) or desmoid tumor is a rare condition, characterized by deep tissue invasion by a monoclonal fibroblastic neoplasm, developed from musculoaponeurotic structures. Surgery is the treatment of choice, but negative margins can hardly been achieved in large tumors, and can lead to major functional disability. AF medical therapy includes nonsteroids anti-inflammatory drugs, tamoxifen, with inconsistent results. Several reports of imatinib efficacy in AF appear in the literature. Here, we describe for the first time a V530I KIT exon 10 mutant that was associated to a dramatic imatinib response in an extraabdominal aggressive fibromatosis. The previously discovered V530I substitution was characterized in the core binding factor AML, but had never been reported in any other condition, so far. In this paper, we discuss the KIT exon 10 mutations or polymorphisms that have been described in a variety of KIT-related conditions, including acute myelogenous leukemia, mastocytosis, and aggressive fibromatosis.
PMID: 20339585 [PubMed - in process]
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The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML.
Science. 2010 Mar 26;327(5973):1650-3
Authors: Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, Zon LI, Armstrong SA
Leukemia stem cells (LSCs) are capable of limitless self-renewal and are responsible for the maintenance of leukemia. Because selective eradication of LSCs could offer substantial therapeutic benefit, there is interest in identifying the signaling pathways that control their development. We studied LSCs in mouse models of acute myelogenous leukemia (AML) induced either by coexpression of the Hoxa9 and Meis1a oncogenes or by the fusion oncoprotein MLL-AF9. We show that the Wnt/beta-catenin signaling pathway is required for self-renewal of LSCs that are derived from either hematopoietic stem cells (HSC) or more differentiated granulocyte-macrophage progenitors (GMP). Because the Wnt/beta-catenin pathway is normally active in HSCs but not in GMP, these results suggest that reactivation of beta-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. beta-catenin is not absolutely required for self-renewal of adult HSCs; thus, targeting the Wnt/beta-catenin pathway may represent a new therapeutic opportunity in AML.
PMID: 20339075 [PubMed - in process]
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[Complex cytogenetic aberrations in a patient with chronic myeloid leukemia: a case report]
Tsitol Genet. 2009 May-Jun;43(3):48-54
Authors: Luk’ianova AS, Pien’kovs’ka-Hrelia B, Masliak ZV
In this article is presented a case of multiple chromosomal aberrations in a patient with CML accelerated phase. Cytogenetic and molecular cytogenetic studies allowed us to determine the presence of t(9;22)(q34;q11) and to identify additional abnormalities such as t(1;2)(p36;p21), del (6)(q21), +del(8)(q22), del(18)(q21), +der (22), some of which are not typical for this kind of neoplasia. This case is compared with publications of the same cases. Our data suggested that detected changes can be correlated with previous treatment regimens and the influence of these changes on progression of disease is discussed.
PMID: 19938637 [PubMed - indexed for MEDLINE]
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Description of a new BCR-ABL point mutation in a CML patient with evolution to lymphoid blast crisis.
Leuk Res. 2010 Apr;34(4):e106-7
Authors: Hokama PO, Capannacci J, Hokama NK, Cliquet MG, Souza MP, Mauad MA, Colturato VA
PMID: 19931180 [PubMed - indexed for MEDLINE]
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A thrombocytosis occurring in Philadelphia positive CML in molecular response to imatinib can reveal an underlying JAK2(V617F) myeloproliferative neoplasm.
Leuk Res. 2010 Apr;34(4):e94-6
Authors: Véronèse L, Tchirkov A, Richard-Pebrel C, Ledoux-Pilon A, Fleury J, Chaleteix C, Goumy C, Gouas L, Berger MG, Vago P, Bay JO, Tournilhac O
PMID: 19833389 [PubMed - indexed for MEDLINE]
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Isolated CNS relapse of CML after bone marrow transplantation.
Leuk Res. 2010 Apr;34(4):e113-4
Authors: Thomas A, Stein CK, Gentile TC, Shah CM
PMID: 19811825 [PubMed - indexed for MEDLINE]
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Major molecular response achieved with dasatinib in a CML patient with F317L BCR-ABL kinase domain mutation.
Leuk Res. 2010 Apr;34(4):e91-3
Authors: Faber E, Mojzikova R, Plachy R, Rozmanova S, Stastny M, Divoka M, Jarosova M, Indrak K, Divoky V
PMID: 19811824 [PubMed - indexed for MEDLINE]
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Chronic myeloid leukemia: a disease of youth in Brazil.
Leuk Res. 2010 Apr;34(4):542-4
Authors: de Campos MG, Arantes Ade M, de Oliveira JS, Chauffaille Mde L
PMID: 19796814 [PubMed - indexed for MEDLINE]
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Posted by rob on March 26, 2010 under Uncategorized |
The real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) has become the method of choice for the quantification of specific mRNAs. This method is fast, extremely sensitive, and accurate, requires only very small amounts of input RNA, and is relatively simple to perform. These characteristics have made it the method of choice for minimal residual disease monitoring such as in chronic myelogenous leukemia (CML). CML comprises approximately 20% of all leukemias and is characterized by a balanced (9;22) chromosomal translocation that results in the formation of a chimeric gene comprised of the BCR (breakpoint cluster region) gene and the ABL oncogene (BCR-ABL fusion gene). The chimeric gene encodes a fusion protein with constitutively increased tyrosine kinase activi…
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We report our experience with 10 CML patients carrying CVTs among 153 newly diagnosed cases followed at our Institution. Results and discussion. Unlike previously published reports, in our series only two CML patients exhibiting CVTs achieved an optimal response to tyrosine kinase inhibitors (TKI) treatment. The remaining eight patients obtained either a suboptimal response or failed drug therapy. Our data suggest that the presence of CVTs at diagnosis might confer an unfavorable clinical outcome, as these genetic alterations might be markers of genomic instability and indicate a higher likelihood of disease progression.
PMID: 20331405 [PubMed - as supplied by publisher] (Source: Acta Oncologica)
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INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance.A dose-esca…
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CONCLUSIONS: This case emphasizes the importance of continuous monitoring of liver function tests even after several years of imatinib therapy and the importance of advising patients to avoid ginseng and any other over-the-counter herbal supplements that may interact with imatinib.
PMID: 20332334 [PubMed - as supplied by publisher] (Source: The Annals of Pharmacotherapy)
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