Posted by rob on February 5, 2011 under Uncategorized | 
Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity.
J Clin Invest. 2011 Jan 4;121(1):396-409
Authors: Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ
Imatinib therapy, which targets the oncogene product BCR-ABL, has transformed chronic myeloid leukemia (CML) from a life-threatening disease into a chronic condition. Most patients, however, harbor residual leukemia cells, and disease recurrence usually occurs when imatinib is discontinued. Although various mechanisms to explain leukemia cell persistence have been proposed, the critical question from a therapeutic standpoint–whether disease persistence is BCR-ABL dependent or independent–has not been answered. Here, we report that human CML stem cells do not depend on BCR-ABL activity for survival and are thus not eliminated by imatinib therapy. Imatinib inhibited BCR-ABL activity to the same degree in all stem (CD34+CD38-, CD133+) and progenitor (CD34+CD38+) cells and in quiescent and cycling progenitors from newly diagnosed CML patients. Although short-term in vitro imatinib treatment reduced the expansion of CML stem/progenitors, cytokine support permitted growth and survival in the absence of BCR-ABL activity that was comparable to that of normal stem/progenitor counterparts. Our findings suggest that primitive CML cells are not oncogene addicted and that therapies that biochemically target BCR-ABL will not eliminate CML stem cells.
PMID: 21157039 [PubMed - indexed for MEDLINE]
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BCR-ABL kinase is dead; long live the CML stem cell.
J Clin Invest. 2011 Jan 4;121(1):22-5
Authors: Perl A, Carroll M
Chronic myeloid leukemia (CML) is a hematopoietic disease characterized by expansion of myeloid blood cells. It is caused by the t(9;22) chromosomal translocation that results in the expression of the fusion tyrosine kinase BCR-ABL. Tyrosine kinase inhibitor (TKI) therapy has led to long-term remissions, but patients remain BCR-ABL+. There is agreement that TKIs do not kill CML stem cells; however, it is controversial whether this is because of a lack of BCR-ABL kinase inhibition in CML stem cells or because CML stem cells do not require BCR-ABL for survival. In this issue of the JCI, Corbin and colleagues provide definitive evidence that BCR-ABL is kinase active in CML stem cells and that TKIs inhibit this kinase activity without affecting CML stem cell survival. Rather, CML stem cells revert to a normal dependence on cytokines for survival and proliferation. These results demonstrate that the CML stem cell is not BCR-ABL addicted and have important implications for developing curative therapeutic approaches to CML.
PMID: 21157035 [PubMed - indexed for MEDLINE]
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Suboptimal response to imatinib according to 2006-2009 European LeukaemiaNet criteria: a ‘grey zone’ at 3, 6 and 12 months identifies chronic myeloid leukaemia patients who need early intervention.
Br J Haematol. 2011 Jan;152(1):119-21
Authors: Breccia M, Orlandi SM, Latagliata R, Grammatico S, Diverio D, Mancini M, Loglisci G, Salaroli A, Federico V, Santopietro M, Alimena G
PMID: 21029071 [PubMed - indexed for MEDLINE]
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Response assessment of patients with chronic myeloid leukemia receiving imatinib mesylate (Glivec) therapy: experience from a single center in a developing country.
Leuk Lymphoma. 2010 Oct;51(10):1850-4
Authors: Medhi K, Raina V, Kumar L, Sharma A, Bakhshi S, Gupta R, Kumar R
Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is a standard of care for chronic myeloid leukemia (CML). There are few publications on responses of patients with CML from the Indian subcontinent. This study analyzed the response rate, progression-free survival (PFS), overall survival (OS), and toxicities in patients with CML given imatinib. Analysis included patients with CML who received imatinib under the GIPAP program at our institution from January 2002 to December 2008. Standard criteria for hematological and cytogenetic responses were used. There were 400 patients, with a median follow-up of 47 months. One hundred and seventy received prior non-imatinib therapy and 230 patients received imatinib upfront. Ninety-five percent of patients achieved complete hematological response. The cumulative best rate of major cytogenetic response was 72%, with 53% complete cytogenetic response and 19% partial cytogenetic response. The estimated PFS and OS at median follow-up for the whole group was 76% and 94%, respectively. Differences in PFS and OS in prior non-imatinib and upfront imatinib groups were not statistically significant. However, better PFS and OS were seen in the upfront imatinib group. Imatinib was well tolerated in our study.
PMID: 20849386 [PubMed - indexed for MEDLINE]
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Valproic acid in the complex therapy of malignant tumors.
Curr Drug Targets. 2010 Mar;11(3):361-79
Authors: Hrebackova J, Hrabeta J, Eckschlager T
Valproic acid (VPA) has been used for epilepsy treatment since the 1970s. Recently, it was demonstrated that it inhibits histone deacetylases (HDAC), modulates cell cycle, induces tumor cell death and inhibits angiogenesis in various tumor models. The exact anticancer mechanisms of VPA remains unclear, but HDAC inhibition, extracellular-regulated kinase activation, protein kinase C inhibition, Wnt-signaling activation, proteasomal degradation of HDAC, possible downregulation of telomerase activity and DNA demethylation participate in its anticancer effect. Hyperacetylation of histones, as a result of HDAC inhibition, seems to be the most important mechanism of VPA’s antitumor action. Preclinical data suggest that the anticancer effect of chemotherapy is augmented when VPA is used in combination with cytostatics. Besides the effects of pretreatment with HDAC inhibitors, which increases the efficiency of 5-aza-2′-deoxycytidine, VP-16, ellipticine, doxorubicin and cisplatin, pre-exposure to VPA increases the cytotoxicity of topoisomerase II inhibitors. There are two suggested cell death mechanisms caused by potentiation of anticancer drugs by HDAC inhibitors that are neither exclusive nor synergistic. The first involves apoptosis and can be both p53 dependent or independent; the second involves mechanisms other than apoptosis. In resistant chronic myeloid leukemia (CML), VPA restores sensitivity to imatinib. We have demonstrated the synergistic effects of VPA and cisplatin in neuroblastoma cells. VPA can be taken orally, crosses the blood brain barrier and can be used for extended periods. Clinical trials in patients with malignancies are being conducted. The use of VPA prior to or together with anticancer drugs may thus prove a beneficial treatment.
PMID: 20214599 [PubMed - indexed for MEDLINE]
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New SRC/ABL inhibitors for chronic myeloid leukemia therapy show selectivity for T315I ABL mutant CD34(+) cells.
Invest New Drugs. 2010 Dec;28(6):876-8
Authors: Santucci MA, Mancini M, Corradi V, Lacobucci I, Martinelli G, Botta M, Schenone S
PMID: 19629392 [PubMed - indexed for MEDLINE]
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In this report, we describe CMV sinusitis in a child with chronic myelogenous leukemia (CML) following bone marrow transplantation. Pediatr Blood Cancer © 2011 Wiley?Liss, Inc. (Source: Pediatric Blood and Cancer)
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Authors: Okada M, Satake A, Kaida K, Taniguchi K, Yoshihara S, Ikegame K, Tamaki H, Soma T, Fujimori Y, Ogawa H
Chronic myelogenous leukemia (CML) is characterized by Philadelphia (Ph) chromosome with a chimeric gene BCR-ABL created by reciprocal t(9:22) (q34;q11) translocation. Variant Ph chromosome translocations involving chromosomes other than 9 and 22 are found in 5-10% of CML cases. We here report a CML patient who carries a four-way Ph chromosome translocation, t(9;22;15;19) (q34;q11;q15;q13). The patient was diagnosed in 1997 and initially treated with hydroxyurea. In 2002, treatment with imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), was started but Ph-positive chromosomes remained at the levels of 42-65%, indicating imatinib failure. In 2006, the point mutatio…
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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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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.
PMID: 21266020 [PubMed - as supplied by publisher] (Source: International Journal of Laboratory Hematology)
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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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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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Authors: Moaddel R, Rosenberg A, Spelman K, Frazier J, Frazier C, Nocerino S, Brizzi A, Mugnaini C, Wainer IW
Cannabinoid Receptors, CB1 and CB2, are therapeutic targets in the treatment of anxiety, obesity, movement disorders, glaucoma and pain. We have developed an on-line screening method for CB1 and CB2 ligands, where cellular membrane fragments of a chronic myelogenous leukemia cell line, (KU-812), were immobilized onto the surface of an open tubular capillary to create a CB1/CB2-OT column. The binding activities of the immobilized CB1/CB2 receptors were established using frontal affinity chromatographic techniques. This is the first report that confirms the presence of functional CB1 and CB2 receptors on KU-812 cells. The data from this study confirm that the CB1/CB2-OT column ca…
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Dasatinib is a potent inhibitor of the BCR-ABL tyrosine kinase and is effective treatment for patients with chronic myelogenous leukemia (CML) resistant to or intolerant of treatment with imatinib. Large granular lymphocytes (LGLs) normally account for only 10–15% of circulating mononuclear cells in adults with most LGLs having an NK-cell phenotype (CD3?, CD16+, CD56+). Proliferation of LGLs has been reported in a small number of patients treated with dasatinib. Mustjoki et al demonstrated that LGL proliferation occurred in both CML and Philadelphia chromosome positive ALL patients treated with dasatinib . Both T- and NK-cell phenotypes were observed in patients with LGL lymphocytosis. In patients with T-cell phenotypes, clonality was demonstrated through T-cell receptor gene rearrange…
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Imatinib, a selective inhibitor of Bcr-Abl tyrosine kinase, has dramatically changed the treatment of chronic myelogenous leukemia (CML). The estimated 6-year overall survival is 95% when only CML-related deaths were considered . However, imatinib is a very expensive agent (standard daily dose (400mg) costs 12,512 yen=140 US$ in Japan). Therefore, in developing countries, allogeneic hematopoietic stem cell transplantation is still performed as a first-line treatment for CML, since many patients are unable to afford the continuing treatment with imatinib. (Source: Leukemia Research)
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This report aims to more accurately define the frequency of the involvement of SRC Family Kinases (SFKs) in imatinib- and dasatinib-resistant CML patients. Clinical samples were analysed during in vivo treatment. We confirmed the high frequency of SFKs involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFKs deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFKs kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine. (Source: Leukemia Research)
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In conclusion, our study points to p57Kip2 as a novel and precocious effector of BCR–ABL targeting drugs. (Source: Carcinogenesis)
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We report a seven?year?old identical twin with CML who developed significant growth delay, as compared to her twin, during five years of TKI therapy. Detailed endocrine evaluation showed acquired growth hormone deficiency, a pathway potentially inhibited by TKIs. Pediatr Blood Cancer © 2010 Wiley?Liss, Inc. (Source: Pediatric Blood and Cancer)
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The Hedgehog (Hh) signaling pathway is critical for cell growth and differentiation during embryogenesis and early development. While it is mostly quiescent in adults, inappropriate reactivation of the Hh pathway has been shown to be involved in the development of cancer. A number of tumor types rely on overexpression of Hh ligands to activate the pathway in a paracrine manner from the tumor to the surrounding stroma. Alternatively, Hh ligands may act on cancer stem cells in some hematopoietic cancers, such as chronic myelogenous leukemia. However, the role of the Hh pathway is best established in tumors, such as basal cell carcinoma and medulloblastoma, where the pathway is activated via mutations. Understanding the contribution of Hh signaling in these various tumor types will be critica…
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