ReviewLeukemia/lymphoma-associated gene fusions in normal individuals

Ms, Brassesco

doi:10.4238/vol7-3gmr486

Cited by 24 publications

(19 citation statements)

References 73 publications

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“…Class I mutations, when their expression is enforced, are capable of conferring cytokine-independent growth activity to cell lines [9,[37][38][39]. In mouse models, HSCs with a high level of BCR-ABL (Class I) enforced by retroviruses showed myeloproliferation, whereas, in healthy human adults, a low level of BCR-ABL transcripts is sometimes detectable [40][41][42]. This suggests that the acquisition of BCR-ABL in HSCs cannot directly provide clonal advantages against normal HSCs.…”

Section: Discussionmentioning

confidence: 99%

The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell

Shima

Miyamoto

Kikushige

et al. 2014

Experimental Hematology

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The cellular properties of leukemia stem cells (LSCs) are achieved at least through Class I and Class II mutations that generate signals for enhanced proliferation and impaired differentiation, respectively. Here we show that in t(8;21) acute myelogenous leukemia (AML), hematopoietic stem cells (HSCs) transform into LSCs via definitively-ordered acquisition of Class II (AML1/ETO) and then Class I (c-KIT mutant) abnormalities. Six t(8;21) AML patients with c-KIT mutants maintaining > 3 years of complete remission were analyzed. At diagnosis, all single LSCs had both AML1/ETO and c-KIT mutations. However, in remission, 16 out of 1,728 CD34(+)CD38(-) HSCs and 89 out of 7,187 single HSC-derived myeloerythroid colonies from these patients had AML1/ETO, whose breakpoints were identical to those found in LSCs. These cells had wild-type c-KIT, which expressed AML1/ETO at a low level, and could differentiate into mature blood cells, suggesting that they may be the persistent preleukemic stem cells. Microarray analysis suggested that mutated c-KIT signaling provides LSCs with enhanced survival and proliferation. Thus, in t(8;21) AML, the acquisition of AML1/ETO is not sufficient, and the subsequent upregulation of AML1/ETO and the additional c-KIT mutant signaling are critical steps for transformation into LSCs.

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Section: Discussionmentioning

confidence: 99%

The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell

Shima

Miyamoto

Kikushige

et al. 2014

Experimental Hematology

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“…Although several examples of aberrant lymphoma-associated gene fusion events are described in B-lymphocyte populations with increasing age, these occurrences are incidental and do not manifest as self-limited, tumor-like expansions. 31 Future studies are necessary to better understand the mechanism by which the oncogenic activation of USP6 generates the unique clinical behavior of NF.…”

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confidence: 99%

Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion

Erickson-Johnson

Chou

Evers

et al. 2011

Laboratory Investigation

346

246

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Nodular fasciitis (NF) is a relatively common mass-forming and self-limited subcutaneous pseudosarcomatous myofibroblastic proliferation of unknown pathogenesis. Due to its rapid growth and high mitotic activity, NF is often misdiagnosed as a sarcoma. While studying the USP6 biology in aneurysmal bone cyst and other mesenchymal tumors, we identified high expression levels of USP6 mRNA in two examples of NF. This finding led us to further examine the mechanisms underlying USP6 overexpression in these lesions. Upon subsequent investigation, genomic rearrangements of the USP6 locus were found in 92% (44 of 48) of NF. Rapid amplification of 5 0 -cDNA ends identified MYH9 as the translocation partner. RT-PCR and direct sequencing revealed the fusion of the MYH9 promoter region to the entire coding region of USP6. Control tumors and tissues were negative for this fusion. Xenografts of cells overexpressing USP6 in nude mice exhibited clinical and histological features similar to human NF. The identification of a sensitive and specific abnormality in NF holds the potential to be used diagnostically. Considering the self-limited nature of the lesion, NF may represent a model of 'transient neoplasia', as it is, to our knowledge, the first example of a self-limited human disease characterized by a recurrent somatic gene fusion event.

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“…The presence of this aberration is however not sufficient for the development of acute lymphoblastic leukemia, once it can also be found in nonneoplastic cells (Janz et al 2003;Brassesco 2008). However, the increased survival of B cells allows the accumulation of the DNA damage, favoring the development of acute lymphoblastic leukemia (Liu et al 1994;Bäsecke et al 2002).…”

Section: Discussionmentioning

confidence: 95%

“…According to Jiang et al (2002), values below 7% can be considered false positives, even though Brassesco (2008) suggested that different lymphoma/leukemiaassociated rearrangements, such as IGH/BCL2, can be found in a small percentage of cells of healthy individuals, without apparent oncogenic consequences.…”

Section: Discussionmentioning

confidence: 97%

Cytogenetic biomonitoring of inhabitants of a large uranium mineralization area: the municipalities of Monte Alegre, Prainha, and Alenquer, in the State of Pará, Brazil

et al. 2010

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Uranium is a natural radioactive metallic element; its effect on the organism is cumulative, and chronic exposure to this element can induce carcinogenesis. Three cities of the Amazon region-Monte Alegre, Prainha, and Alenquer-in North Brazil, are located in one of the largest uranium mineralization areas of the world. Radon is a radioactive gas, part of uranium decay series and readily diffuses through rock. In Monte Alegre, most of the houses are built of rocks removed from the Earth's crust in the forest, where the uranium reserves lie. The objective of the present work is to determine the presence or absence of genotoxicity and risk of carcinogenesis induced by natural exposure to uranium and radon in the populations of these three cities. The frequency of micronuclei (MN) and chromosomal aberrations (CA) showed no statistically significant differences between the control population and the three study populations (P > 0.05). MN was also analyzed using the fluorescence in situ hybridization (FISH) technique, with a centromere-specific probe. No clastogenic and/or aneugenic effects were found in the populations. Using FISH analysis, other carcinogenesis biomarkers were analyzed, but neither the presence of the IGH/BCL2 translocation nor an amplification of the MYC gene and 22q21 region was detected. Clastogenicity and DNA damage were also not found in the populations analyzed using the alkaline comet assay. The mitotic index showed no cytotoxicity in the analyzed individuals' lymphocytes. Once we do not have data concerning radiation doses from other sources, such as cosmic rays, potassium, thorium, or anthropogenic sources, it is hard to determine if uranium emissions in this geographic region where our study population lives are too low to cause significant DNA damage. Regardless, genetic analyses suggest that the radiation in our study area is not high enough to induce DNA alterations or to interfere with mitotic apparatus formation. It is also possible that damages caused by radiation doses undergo cellular repair.

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ReviewLeukemia/lymphoma-associated gene fusions in normal individuals

Cited by 24 publications

References 73 publications

The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell

The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell

Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion

Cytogenetic biomonitoring of inhabitants of a large uranium mineralization area: the municipalities of Monte Alegre, Prainha, and Alenquer, in the State of Pará, Brazil

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