Posted by rob on October 15, 2009 under Uncategorized | 
The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia.
Cancer Cell. 2009 Sep 8;16(3):232-45
Authors: Klemm L, Duy C, Iacobucci I, Kuchen S, von Levetzow G, Feldhahn N, Henke N, Li Z, Hoffmann TK, Kim YM, Hofmann WK, Jumaa H, Groffen J, Heisterkamp N, Martinelli G, Lieber MR, Casellas R, Müschen M
Chronic myeloid leukemia (CML) is induced by BCR-ABL1 and can be effectively treated for many years with Imatinib until leukemia cells acquire drug resistance through BCR-ABL1 mutations and progress into fatal B lymphoid blast crisis (LBC). Despite its clinical significance, the mechanism of progression into LBC is unknown. Here, we show that LBC but not CML cells express the B cell-specific mutator enzyme AID. We demonstrate that AID expression in CML cells promotes overall genetic instability by hypermutation of tumor suppressor and DNA repair genes. Importantly, our data uncover a causative role of AID activity in the acquisition of BCR-ABL1 mutations leading to Imatinib resistance, thus providing a rationale for the rapid development of drug resistance and blast crisis progression.
PMID: 19732723 [PubMed - indexed for MEDLINE]
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Imatinib resistance and progression of CML to blast crisis: somatic hypermutation AIDing the way.
Cancer Cell. 2009 Sep 8;16(3):174-6
Authors: Strout MP, Schatz DG
Very little is known about how acquired oncogenic mutations arise. In this issue of Cancer Cell, Klemm and colleagues present evidence supporting a role for the antibody diversification enzyme activation-induced deaminase (AID) in the generation of mutations associated with disease progression and drug resistance in chronic myeloid leukemia.
PMID: 19732715 [PubMed - indexed for MEDLINE]
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Targeted cancer therapy: promise and reality.
Adv Cancer Res. 2007;97:295-319
Authors: Klein S, Levitzki A
Signal transduction therapy for cancer targets specific molecular elements that are essential for survival of the tumor. Gleevec has a profound effect on early phase chronic myeloid leukemia because it inhibits the major driving factor of the tumor, BCR-ABL. Almost all other cancers depend on several factors, and blocking a single signal transduction factor is largely ineffective. Effective signal transduction therapy will entail finding the appropriate combination of signal transduction inhibitors for each cancer. We discuss the use of preclinical animal models to predict successful signal transduction therapy in the clinic, and conclude that their utility is limited.
PMID: 17419951 [PubMed - indexed for MEDLINE]
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Posted by rob on October 12, 2009 under Uncategorized |
Authors: Bonovolias ID, Tsiftsoglou AS
Imatinib is a targeted selective inhibitor of chimaeric Bcr-Abl tyrosine kinase developed for effective therapy of chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) patients. Unfortunately, evidence now exists to indicate that a portion of such patients treated with imatinib acquire resistance and subsequently relapse. To understand the heterogeneous basis of imatinib resistance, we have investigated the possible mechanism(s) via which hemin, a key regulator of hematopoiesis that is converted to heme intracellularly, renders CML cells less susceptible to imatinib. Hemin at 30-90 aM protected a substantial proportion (>40%) of human Bcr-Abl(+) CML cells (K-562 and KU-812) from imatinib-induced cell killing by increasing the…
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In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNFalpha-treated cells and which genes display an interaction effect between heteronemin and TNFalpha. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor kappaB (NF-kappaB) signaling cascade. We confirmed in silico experiments regarding NF-kappaB inhibition by reporter gene anal…
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Enlarged and Prominent Nucleus May be Indicative of Tetraploidy: A Laboratory Study of a Rare Near-tetraploidy in a Child Patient With Acute Myelogenous Leukemia AML-M4.
J Pediatr Hematol Oncol. 2009 Oct 7;
Authors: Zhang JH, Zheng YC, Wang YX, Zhang JY, Liu ZG
Near-tetraploidy is a rare cytogenetic abnormality in myelocytic malignancies in children and its significance is unknown. To investigate the pathologic characteristics of a near-tetraploidy in a child with acute myelogenous leukemia (AML-M4), bone marrow smears were prepared for morphologic analysis. Bone marrow samples were collected at presentation for flow cytometry, prepared by short-term (24 h) unstimulated culture and R-banding for conventional cytogenetic assay. We have performed a multifactorial analysis of the laboratory test results. In this case, the chromosomal analysis (R-banding) demonstrated a near-tetraploidy. Combined with morphologic and immunophenotypic results, the diagnosis was established as acute myelogenous leukemia (AML-M4). Near-tetraploidy is an uncommon cytogenetic finding, and the experience of this case further emphasizes the importance of the laboratory diagnostic methods.
PMID: 19816206 [PubMed - as supplied by publisher]
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Heteronemin, a spongean sesterterpene, inhibits TNFalpha-induced NF-kappaB activation through proteasome inhibition and induces apoptotic cell death.
Biochem Pharmacol. 2009 Oct 5;
Authors: Schumacher M, Cerella C, Eifes S, Chateauvieux S, Morceau F, Jaspars M, Dicato M, Diederich M
In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNFalpha-treated cells and which genes display an interaction effect between heteronemin and TNFalpha. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor kappaB (NF-kappaB) signaling cascade. We confirmed in silico experiments regarding NF-kappaB inhibition by reporter gene analysis, electrophoretic mobility shift analysis and IkappaB degradation. In order to assess the underlying molecular mechanisms, we determined that heteronemin inhibits both trypsin and chymotrypin-like proteasome activity at an IC 50 of 0.4muM. Concomitant to the inhibition of the NF-kappaB pathway, we also observed a reduction in cellular viability. Heteronemin induces apoptosis as shown by Annexin V/propidium iodide staining, nuclear morphology analysis, procaspase 3, -8 and -9 and poly(ADP-ribose) polymerase (PARP) cleavage as well as truncation of Bid. Altogether, results show that this compound has potential as anti-inflammatory and anti-cancer agent.
PMID: 19814997 [PubMed - as supplied by publisher]
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The allometry of chronic myeloid leukemia.
J Theor Biol. 2009 Aug 7;259(3):635-40
Authors: Pacheco JM, Traulsen A, Dingli D
Chronic myeloid leukemia (CML) is an acquired neoplastic hematopoietic stem cell (HSC) disorder characterized by the expression of the BCR-ABL oncoprotein. This gene product is necessary and sufficient to explain the chronic phase of CML. The only known cause of CML is radiation exposure leading to a mutation of at least one HSC, although the vast majority of patients with CML do not have a history of radiation exposure. Nonetheless, in humans, significant radiation exposure (after exposure to atomic bomb fallout) leads to disease diagnosis in 3-5 years. In murine models, disease dynamics are much faster and CML is fatal over the span of a few months. Our objective is to develop a model that accounts for CML across all mammals. In the following, we combine a model of CML dynamics in humans with allometric scaling of hematopoiesis across mammals to illustrate the natural history of chronic phase CML in various mammals. We show how a single cell can lead to a fatal illness in mice and humans but a higher burden of CML stem cells is necessary to induce disease in larger mammals such as elephants. The different dynamics of the disease is rationalized in terms of mammalian mass. Our work illustrates the relevance of animal models to understand human disease and highlights the importance of considering the re-scaling of the dynamics that accrues to the same biological process when planning experiments involving different species.
PMID: 19362566 [PubMed - indexed for MEDLINE]
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Posted by rob on October 8, 2009 under Uncategorized |
Hemin counteracts the repression of Bcl-2 and NrF2 genes and the cell killing induced by imatinib in human Bcr-Abl(+) CML cells.
Oncol Res. 2009;17(11-12):535-47
Authors: Bonovolias ID, Tsiftsoglou AS
Imatinib is a targeted selective inhibitor of chimaeric Bcr-Abl tyrosine kinase developed for effective therapy of chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) patients. Unfortunately, evidence now exists to indicate that a portion of such patients treated with imatinib acquire resistance and subsequently relapse. To understand the heterogeneous basis of imatinib resistance, we have investigated the possible mechanism(s) via which hemin, a key regulator of hematopoiesis that is converted to heme intracellularly, renders CML cells less susceptible to imatinib. Hemin at 30-90 aM protected a substantial proportion (>40%) of human Bcr-Abl(+) CML cells (K-562 and KU-812) from imatinib-induced cell killing by increasing the imatinib IC50 value, reducing DNA damage, and promoting erythroid differentiation. RT-PCR assessment of RNA transcripts encoded by human GAPDH, Ggamma-globin, Bcr-Abl, HO-2, Hpr-6, CEBPa, Bcl-2a, Bcl-2b, and Nrf2 genes revealed that hemin selectively counteracted the repression of antiapoptotic Bcl-2a, Bcl-2b, and Nrf2 genes in imatinib-treated cells. These genes are markedly repressed by imatinib alone in human K-562 CML cells. Hemin, however, had no detectable effect on the expression of the Bcr-Abl gene. Moreover, inhibition of de novo heme biosynthesis by succinyl-acetone enhanced the killing effect of imatinib. These data clearly indicate that: (a) cellular heme resulted from de novo biosynthesis and hemin uptake alters the developmental stage of human Bcr-Abl(+) CML cells and their susceptibility to imatinib; (b) cellular heme counteracts the ability of imatinib to repress Bcl-2 and Nrf2 gene expression; and (c) inhibitors of de novo biosynthesis can be developed and combined with imatinib to enhance its antileukemic activity.
PMID: 19806784 [PubMed - in process]
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Posted by rob on October 6, 2009 under Uncategorized |
Acute myelogenous leukemia in a child with HIV infection.
Eur J Pediatr. 2009 Oct 3;
Authors: Tullu MS, Date NB, Ghildiyal RG, Modi CJ
The occurrence of acute myelogenous leukemia (AML) in HIV-infected patients is extremely rare with only adult patients reported so far. Our patient was a 7-year-old male who presented with fever and cough since 1 month with six episodes of intermittent hemoptysis. The child also had recurrent parotid swellings, melena, and purulent otitis media. Investigations revealed anemia (hemoglobin of 8.9 g/dl), thrombocytopenia (platelet count of 21,000 cells per microliter), and positive HIV antibody (perinatal transmission). The patient’s bone marrow aspiration and biopsy suggested AML, and the leukemia panel 1 study showed CD13, CD33, CD34, and HLA DR-positive AML with CD7 expression. The child was given supportive treatment but succumbed to the disease. AML can occur in pediatric patients with HIV infection. A high index of suspicion of hematological malignancies should be kept in mind for patients presenting with cytopenias. This is the first HIV-infected pediatric patient (<12 years) with AML reported in the medical literature.
PMID: 19802631 [PubMed - as supplied by publisher]
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[Xanthelasma and juvenile xanthogranuloma in a 7-year-old boy.]
Ann Dermatol Venereol. 2009 Oct;136(10):723-6
Authors: Le Bidre E, Delage M, Lejars O, Machet MC, Lorette G, Maruani A
BACKGROUND: Palpebrum xanthelasma is the most common type of xanthoma seen in adults but it is extremely rare in children. We report an original case of bilateral xanthelasma palpebrarum associated with juvenile xanthogranuloma (JXG) in a 7-year-old child. Only two cases of xanthelasma in children have been described to date. The association of xanthelasma and JXG has never been described. PATIENTS AND METHODS: A 7-year-old boy presented xanthelasmas on both eyelids. At the same time, pinkish JXG papules appeared on the child’s trunk. The boy had been diagnosed at the age of 10 months with myelogenous leukaemia, which was in remission. He also had a familial history of hypercholesterolaemia. The skin lesions were removed and microscopic examination confirmed the diagnosis of xanthelasmas and JXG. DISCUSSION: This patient’s presentation is unusual in several respects: the presence of xanthelasma in a child, appearance of JXG at an advanced age, and the association of these two diseases in a child with a past history of leukaemia. The occurrence of these skin lesions did not appear to be linked to the history of malignant blood disease in this patient.
PMID: 19801258 [PubMed - in process]
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[Detection of JAK2V617F mutation and its clinical significance in 80 patients with M2 acute myelogenous leukemia]
Zhonghua Zhong Liu Za Zhi. 2009 May;31(5):366-70
Authors: Shen YM, Chao HY, Zhang R, Li WY, Feng YF, Zhu ZL, Xue YQ
OBJECTIVE: To explore the prevalence and prognostic significance of JAK2V617F gene mutation in acute myelogenous leukemia M2 (AML-M2) patients. METHODS: Allele specific polymerase chain reaction (PCR) was used to detect JAK2 gene mutation. RESULTS: Of 80 de novo AML-M2 patients, 6 at the time of first diagnosis and 1 at relapse were found to have JAK2V617F gene mutation (8.8%, 7/80). Morphologically, the whole blood and bone marrow of the 7 AML-M2 patients with JAK2V617F gene mutation presented a picture of acute leukemia instead of myeloproliferative disorders. Immunophenotypically, bone marrow samples showed myelogenous linage expression. Complete remission was obtained in 4 of 5 AML-M2 patients with JAK2V617F mutation who received treatment, while one patient had no response to the treatment. Follow-up was performed in all the 5 patients, with a median survival of 18.5 months in 4 patients. CONCLUSION: JAK2V617F gene mutation, as a type-1 mutation, might not be an initial event in the pathogenesis of acute myelogenous leukemia, and its presentation does not mean a poor prognosis in de novo AML patients.
PMID: 19799086 [PubMed - in process]
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Efficient activation of LRH-1-specific CD8+ T-cell responses from transplanted leukemia patients by stimulation with P2X5 mRNA-electroporated dendritic cells.
J Immunother. 2009 Jul-Aug;32(6):539-51
Authors: Overes IM, Fredrix H, Kester MG, Falkenburg JH, van der Voort R, de Witte TM, Dolstra H
Alloreactive CD8+ T cells targeting minor histocompatibility antigens (MiHA) on malignant cells of the recipient play a pivotal role in graft-versus-tumor responses observed after allogeneic stem cell transplantation and donor lymphocyte infusion (DLI). However, these MiHA-specific CD8+ T-cell responses do not result in complete eradication of tumor cells in all patients. Furthermore, CD8+ memory T cells persisting after DLI do not always efficiently expand with recurrence of the disease. Adjuvant immunotherapy using dendritic cells (DC) loaded with hematopoietic-restricted MiHA may boost antitumor CD8+ T-cell immunity without inducing graft-versus-host disease. Here, we explored the use of mRNA-electroporated DC to stimulate MiHA-specific CD8+ T-cell responses. We demonstrate that electroporation of mature DC with P2X5 mRNA encoding for hematopoietic-restricted MiHA LRH-1 results in high expression of both mRNA and protein, and has no negative effect on the mature phenotype and migratory capacity of the DC. Furthermore, these DC can efficiently stimulate LRH-1-specific CD8+ effector T cells to proliferate and produce interferon-gamma. In addition, LRH-1-specific CD8+ memory T cells that are present in patient-derived peripheral blood mononuclear cells at long periods post-DLI can be effectively activated by stimulation with P2X5 mRNA-electroporated DC to proliferate and degranulate upon target cell recognition. These results indicate that adjuvant immunotherapy using DC electroporated with mRNA encoding hematopoietic-restricted MiHA mismatched between patients and donors may enhance the graft versus tumor response induced by stem cell transplantation and DLI.
PMID: 19483655 [PubMed - indexed for MEDLINE]
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[Effect of G-CSF on the proliferation and differentiation of bcr/abl(+)-CD34+ cells from CML patients]
Zhonghua Xue Ye Xue Za Zhi. 2007 Nov;28(11):762-5
Authors: Li CY, Meng FY, Sun QX, Fu YB, Jiang QL, Yi ZS, Song LL
OBJECTIVE: To study the effect of granulocyte colony-stimulating factor (G-CSF) on the proliferation and differentiation of bcr/abl(+)-CD34+ cells. METHODS: bcr/abl(+)-CD34+ cells were isolated from bone marrow of chronic myelocytic leukemia (CML) patients and were treated with 0, 10, 100, 1000 ng/ml of G-CSF for 48, 96, 144 hs. CD34 cells from normal bone marrow were used as controls. Cell proliferation was determined by trypan blue dye exclusion, cell-cycle and antigen differentiation were determined by flow cytometry and cell morphology was observed under light microscope. RESULTS: The number of bcr/abl(+)-CD34+ cells was increased obviously in all groups. After cultured for 48 and 96 h, the number of bcr/abl(+)-CD34+ cells at G-CSF 10 ng/ml group was significantly higher than that in G-CSF 0 ng/ml group (P < 0.05) , the number of normal CD34 cells was increased only in the presence of G-CSF. After cultured for 48, 96 and 144 h, the cell number in G-CSF 100 ng/ml group was significantly higher than that in G-CSF 0 ng/ml group (P < 0.05, P < 0.01, P < 0.01, respectively). After cultured for 144 h, the cell percentages in G0/G1 phase for bcr/abl(+)-CD34+ cells in G-CSF 10, 100, 1000 ng/ml groups were significantly less than that in G-CSF 0 ng/ml group (P < 0. 05), and that for normal CD34 cells in G-CSF 10, 100, 1000 ng/ml groups were significantly less than that of G-CSF 0 ng/ml group after cultured for 48 and 96 h. The expressions of CD34 on bcr/abl(+)-CD34+ cells and normal CD34+ cells were decreased along with the culture duration, accompanied by the expression of CD33 and CD13 increased first and decreased later, which was not correlated with the concentration of G-CSF. Both bcr/abl(+)-CD34+ cells and normal CD34+ cells showed mature morphology along with proliferation and differentiation. CONCLUSIONS: G-CSF promotes proliferation of both bcr/abl(+)-CD34+ cells and normal CD34+ cells, but not necessary for the former, and the former differentiates more rapidly than the latter does, but both was independent of G-CSF.
PMID: 18457269 [PubMed - indexed for MEDLINE]
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Posted by rob on October 3, 2009 under Uncategorized |
Impressive response rates and the good tolerability have allowed imatinib to become the gold standard frontline therapy for all CML patients in the early chronic phase. Optimal outcomes are attained with more than two thirds of the CML cases treated with standard dose imatinib (400 mg daily). Criteria to establish failure and suboptimal responses to imatinib have been defined. Treatment guidelines have also suggested imatinib dose escalation based on clinical assessments of disease response. However, despite all the effort to optimize therapy with imatinib, cases of real resistance exist. For imatinib resistant and intolerant cases, second generation powerful tyrosine kinase inhibitors (TKIs) have been developed and registered. Sequential kinase inhibitor therapy is used to overcome resist…
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Authors: Colosetti P, Puissant A, Robert G, Luciano F, Jacquel A, Gounon P, Cassuto JP, Auberger P
Autophagy is a highly conserved catabolic process for the elimination and recycling of organelles and macromolecules, characterized by the formation of double-membrane vesicles called autophagosomes. To date, the function of autophagy in cell differentiation is poorly documented. Here, we investigated the possibility that megakaryocytic differentiation of the Chronic Myelogenous Leukemia (CML) cell line K562, a process known to be accompanied by accumulation of vacuoles inside the cells, might involve autophagy. Using various complementary approaches, we show that the combination of the phorbol ester PMA and the p38(MAPK) inhibitor SB202190 (SB), which engaged a majority of K562 cells tow…
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Suboptimal responses to imatinib in chronic myelogenous leukemia: what are they and how do they affect treatment?
Clin J Oncol Nurs. 2009 Oct;13(5):537-42
Authors: Allen-Bard S
First-line treatment for chronic myelogenous leukemia (CML) is imatinib, but some patients do not respond or develop resistance to the drug, leading to suboptimal responses. Dasatinib and nilotinib are approved second-line compounds for patients experiencing imatinib failure. In a prospective comparison of dasatinib with high-dose imatinib in patients who did not respond to first-line imatinib, dasatinib was more effective and well tolerated. Nilotinib also is effective, but cross-intolerance does occur in a substantial number of patients. This article explores the importance of suboptimal response to imatinib and the appropriate second-line therapy as well as nursing implications for caring for patients with CML.
PMID: 19793710 [PubMed - in process]
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NCCN task force report: molecular markers in leukemias and lymphomas.
J Natl Compr Canc Netw. 2009 Jul;7 Suppl 4:S1-34, quiz S35-6
Authors: Radich JP, Zelenetz AD, Chan WC, Croce CM, Czuczman MS, Erba HP, Horning SJ, Houldsworth J, Smith BD, Snyder DS, Sundar HM, Wetzler M, Winter JN
The introduction of targeted therapies has revolutionized treatment and improved outcomes in patients with leukemias and lymphomas. However, many patients experience relapse caused by the persistence of residual malignant cells. Cytogenetic and molecular techniques are increasingly being used to assess and quantify minimal residual disease (MRD). The emergence of advanced technologies has led to the discovery of multiple novel molecular markers that can be used to detect MRD and predict outcome in patients with leukemias and lymphomas. Gene expression signatures that predict clinical outcomes in patients with non-Hodgkin’s lymphoma have been identified. In chronic myelogenous leukemia, molecular monitoring has become more important in assessing response and detecting resistance to therapy. In acute leukemias, several new markers have shown potential in prognostication and monitoring treatment. In leukemias and lymphomas, microRNAs have been identified that may be useful in diagnostics and prognostication. To address these issues, the National Comprehensive Cancer Network (NCCN) organized a task force consisting of a panel of experts in leukemia and lymphoma to discuss recent advances in the field of molecular markers and monitoring MRD.
PMID: 19635230 [PubMed - in process]
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Rendering the leukemia cell susceptible to attack.
N Engl J Med. 2009 Sep 24;361(13):1307-9
Authors: Sipkins DA
PMID: 19776414 [PubMed - indexed for MEDLINE]
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Attacking cancer at its root.
Cell. 2009 Sep 18;138(6):1051-4
Authors: Thompson CB
This year the Lasker DeBakey Clinical Research Award will be shared by Brian Druker, Nicholas Lydon, and Charles Sawyers for their development of a targeted molecular therapy for treating chronic myeloid leukemia. Their work demonstrated the ability of drugs directed against cancer-causing oncogenes to turn a rapidly fatal malignancy into a manageable chronic disease.
PMID: 19766556 [PubMed - indexed for MEDLINE]
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