Fused transcript of abl and bcr genes in chronic myelogenous leukaemia

Shtivelman, Emma; Lifshitz, Batia; Gale, Robert Peter; Canaani, Eli

doi:10.1038/315550a0

Cited by 1,503 publications

(692 citation statements)

References 30 publications

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“…CML cells also have the potential to generate acute leukemias of myeloid and lymphoid lineage during the blast crisis 41,42 . At the molecular level, CML is characterized by the BCR-ABL oncogenic fusion, which can be detected through all lineages of differentiation of CML cells, including the CD34+ stem cell compartment, pointing out to this leukemia as a prototype of stem cell disorder [41][42][43][44] . However, recent studies have indicated that the granulocyte-macrophage progenitor cells from patients with CML in blast crisis presented self-renewal capacity, a cell compartment which normally has not this property 45 .…”

Section: Hematopoietic Stem Cells As Targets Of Transforming Mutationmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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Section: Hematopoietic Stem Cells As Targets Of Transforming Mutationmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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“…1928) and David Hungerford ) discovered the Philadelphia chromosome, 9 which was later shown to harbor an oncogenic BCR-ABL1 fusion transcript, which is the disease-causing mutation in chronic myelogenous leukemia. [10][11][12][13][14] Accordingly, PMF is currently grouped with PV and ET as BCR-ABL1-negative MPN. 15 In addition to the previously mentioned JAK2V617F, 7 PMF and the other BCR-ABL1-negative MPNs are characterized by many other somatic mutations, including MPL, TET2, ASXL1, CBL, IDH1, IDH2, IKZF1, LNK, EZH2, DNMT3A, CUX1, and SF3B1 mutations.…”

mentioning

confidence: 99%

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

Tefferi

Lasho

Jimma

et al. 2012

Mayo Clinic Proceedings

187

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Objective: To share our decades of experience with primary myelofibrosis and underscore the importance of outcomes research studies in designing clinical trials and interpreting their results. Patients and Methods: One thousand consecutive patients with primary myelofibrosis seen at Mayo Clinic between November 4, 1977, and September 1, 2011, were considered. The International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus were applied for risk stratification. Separate analyses were included for patients seen at time of referral (Nϭ1000), at initial diagnosis (Nϭ340), and within or after 1 year of diagnosis (Nϭ660). Results: To date, 592 deaths and 68 leukemic transformations have been documented. Parameters at initial diagnosis vs time of referral included median age (66 vs 65 years), male sex (61% vs 62%), red cell transfusion need (24% vs 38%), hemoglobin level less than 10 g/dL (38% vs 54%), platelet count less than 100 ϫ 10 9 /L (18% vs 26%), leukocyte count more than 25 ϫ 10 9 /L (13% vs 16%), marked splenomegaly (21% vs 31%), constitutional symptoms (29% vs 34%), and abnormal karyotype (31% vs 41%). Mutational frequencies were 61% for JAK2V617F, 8% for MPLW515, and 4% for IDH1/2. DIPSS-plus risk distributions at time of referral were 10% low, 15% intermediate-1, 37% intermediate-2, and 37% high. The corresponding median survivals were 17.5, 7.8, 3.6, and 1.8 years vs 20.0, 14.3, 5.3, and 1.7 years for patients younger than 60 years of age. Compared with both DIPSS and IPSS, DIPSS-plus showed better discrimination among risk groups. Five-year leukemic transformation rates were 6% and 21% in low-and high-risk patients, respectively. Conclusion: The current document should serve as a valuable resource for patients and physicians and provides context for the design and interpretation of clinical trials.

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“…BCR-ABL displays constitutive kinase activity, which results in the deregulated activation of signaling cascades that promote cell proliferation and survival (Shtivelman et al, 1985;. The first compound that successfully inhibited the aberrant BCR-ABL kinase activity and displayed clinical efficacy was imatinib mesylate (Druker, 2001), which has considerably increased the survival rate of CML patients (88% for 6 years) and decreased the need of hematopoietic stem cell transplantation (Hochhaus et al, 2009).…”

Section: Current Therapeutic Paradigms To Treat Cancermentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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Fused transcript of abl and bcr genes in chronic myelogenous leukaemia

Cited by 1,503 publications

References 30 publications

Somatic stem cells and the origin of cancer

Somatic stem cells and the origin of cancer

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

Towards novel paradigms for cancer therapy

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