Leukemia patient-derived lymphoblastoid cell lines exhibit increased induction of leukemia-associated transcripts following high-dose irradiation

Spencer, Andrew; Granter, Neil

doi:10.1016/s0301-472x(99)00082-x

Cited by 11 publications

(10 citation statements)

References 22 publications

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“…Homologous sequences have been identified on chromosomes 9 and 22 that might facilitate aberrant recombination [15]. Moreover, cell lines subjected to irradiation in vitro produce BCR-ABL1 transcripts [16,17,18], and persons receiving high-dose irradiation, be it after the explosion of atomic bombs in Japan or after radiotherapy, are at increased risk of developing CML [19]. Thus, radiation exposure could be a contributory factor; however, whether this is relevant to all new cases of CML is unknown.…”

Section: Formation Of the Bcr-abl1 Fusion Genementioning

confidence: 99%

BCR-ABL in Chronic Myelogenous Leukemia – How Does It Work?

Goldman

Melo²

2008

Acta Haematol

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The discovery of the BCR-ABL fusion gene on the Philadelphia (Ph) chromosome in 1985 was the start of a new era in understanding the molecular basis of hematologic malignancies. It provided the rationale for producing first imatinib and then a series of small molecules designed to inhibit the tyrosine kinase activity of the Bcr-Abl oncoprotein, all of which can induce complete cytogenetic remissions in the majority of patients with chronic myelogenous leukemia (CML) in the chronic phase. However, we still do not know for sure whether the BCR-ABL fusion gene is really the initiating lesion for the chronic phase of CML and we have an incomplete understanding of the so-called genomic instability that underlies the production of the fusion gene and predisposes the Ph-positive clone to acquire further genetic events that lead to advanced-phase disease. Moreover, it is clear that though some of the mutant Ph-positive subclones that develop in patients taking tyrosine kinase inhibitors (TKIs) are the direct cause of the resistance observed, in other cases, its cause is unclear. It is likely that in the next few years we will see (1) improved methods for predicting responses to TKIs, (2) the use of TKIs in combination with other effective molecules such as farnesyl transferase inhibitors, and (3) a gradual reduction in the proportion of chronic-phase patients resistant to therapy.

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Section: Formation Of the Bcr-abl1 Fusion Genementioning

confidence: 99%

BCR-ABL in Chronic Myelogenous Leukemia – How Does It Work?

Goldman

Melo²

2008

Acta Haematol

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“…Second, the Ph Ϫ cells are polyclonal in most cases studied thus far, 7,8 By contrast, studies in Epstein-Barr virus (EBV)-transformed Ph Ϫ B-lymphoblastoid cell lines established from patients with CML showed skewing toward the type of glucose-6-phosphate dehydrogenase (G-6PD) isoenzyme of the CML clone in a subset of patients with CML 9,10 ; this implies that, in these cases, the Ph translocation arose in an already clonal population. Cytogenetic abnormalities 9 as well as an increased propensity to radiation-induced chromosomal translocations 11 have also been described in such lines. Furthermore, clonal chromosomal abnormalities are occasionally seen in Ph Ϫ metaphases from cytogenetic responders to IFN-␣.…”

Section: Introductionmentioning

confidence: 98%

Emergence of clonal cytogenetic abnormalities in Ph−cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority

Bumm

Müller

Al-Ali

et al. 2003

Blood

212

163

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Chronic myelogenous leukemia (CML) is characterized by the presence of a BcrAbl fusion protein with deregulated tyrosine kinase activity that is required for maintaining the malignant phenotype. Imatinib, a selective inhibitor of Bcr-Abl, induces major cytogenetic remission (MCR) or complete cytogenetic remission (CCR) in the majority of patients with CML in first chronic phase. However, thorough re-evaluation of cytogenetics in a cohort of patients in MCR or CCR demonstrated clonal karyotypic abnormalities in more than 10% of cases, some of which were clinically associated with a myelodysplastic syndrome (MDS). Further analysis identified previous exposure to cytarabine and idarubicin as significant risk factors for the subsequent occurrence of abnormalities in Philadelphia chromosome-negative (Ph ؊ ) cells. To investigate if cytogenetically normal but clonal hematopoiesis might be present in other patients in cytogenetic remission, we studied X-chromosome inactivation as a marker of clonality by polymerase chain reaction analysis of the human androgen receptor (HUMARA). We find that imatinib restores a polyclonal pattern in most patients in CCR and MCR. Nonetheless, our results are consistent with the notion that targeted therapy of CML with imatinib favors the manifestation of Ph ؊ clonal disorders in some patients. They indicate that patients on imatinib should be followed with conventional cytogenetics, even after induction of

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“…The chimeric gene, bcr/abl, can be induced directly within targeted haematopoietic cells in vitro by very high (i.e. 50–100 Gy) doses of low-LET irradiation (Ito et al., 1993b; Spencer and Granter, 1999), thus providing direct evidence of its induction by x irradiation in vivo. However, the relevance of the latter studies has been questioned because the ‘inductive’ doses used in these experiments are at least an order of magnitude greater than what one would normally perceive as being ‘biologically relevant’.…”

Section: Annex a Haematopoietic Tissues: Role Played By Stem Cells Amentioning

confidence: 99%

ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection

et al. 2015

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This report provides a review of stem cells/progenitor cells and their responses to ionising radiation in relation to issues relevant to stochastic effects of radiation that form a major part of the International Commission on Radiological Protection's system of radiological protection. Current information on stem cell characteristics, maintenance and renewal, evolution with age, location in stem cell 'niches', and radiosensitivity to acute and protracted exposures is presented in a series of substantial reviews as annexes concerning haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. This foundation of knowledge of stem cells is used in the main text of the report to provide a biological insight into issues such as the linear-no-threshold (LNT) model, cancer risk among tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age. Knowledge of the biology and associated radiation biology of stem cells and progenitor cells is more developed in tissues that renew fairly rapidly, such as haematopoietic tissue, intestinal mucosa, and epidermis, although all the tissues considered here possess stem cell populations. Important features of stem cell maintenance, renewal, and response are the microenvironmental signals operating in the niche residence, for which a well-defined spatial location has been identified in some tissues. The identity of the target cell for carcinogenesis continues to point to the more primitive stem cell population that is mostly quiescent, and hence able to accumulate the protracted sequence of mutations necessary to result in malignancy. In addition, there is some potential for daughter progenitor cells to be target cells in particular cases, such as in haematopoietic tissue and in skin. Several biological processes could contribute to protecting stem cells from mutation accumulation: (a) accurate DNA repair; (b) rapidly induced death of injured stem cells; (c) retention of the DNA parental template strand during divisions in some tissue systems, so that mutations are passed to the daughter differentiating cells and not retained in the parental cell; and (d) stem cell competition, whereby undamaged stem cells outcompete damaged stem cells for residence in the niche. DNA repair mainly occurs within a few days of irradiation, while stem cell competition requires weeks or many months depending on the tissue type. The aforementioned processes may contribute to the differences in carcinogenic radiation risk values between tissues, and may help to explain why a rapidly replicating tissue such as small intestine is less prone to such risk. The processes also provide a mechanistic insight relevant to the LNT model, and the relative and absolute risk models. The radiobiological knowledge also provides a scientific insight into discussions of the dose and dose-rate effectiveness factor currently used in radiological protection guidelines. In addition, the biological information contributes potential reasons for the ...

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Leukemia patient-derived lymphoblastoid cell lines exhibit increased induction of leukemia-associated transcripts following high-dose irradiation

Cited by 11 publications

References 22 publications

BCR-ABL in Chronic Myelogenous Leukemia – How Does It Work?

BCR-ABL in Chronic Myelogenous Leukemia – How Does It Work?

Emergence of clonal cytogenetic abnormalities in Ph−cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority

ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection

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