AML1 mutations induced MDS and MDS/AML in a mouse BMT model

Watanabe‐Okochi, Naoko; Kitaura, Jiro; Ono, Ryoichi; Harada, Hironori; Harada, Yuka; Komeno, Yukiko; Nakajima, Hitoshi; Nosaka, Tetsuya; Inaba, Toshiya; Kitamura, Toshio

doi:10.1182/blood-2007-01-068346

Cited by 143 publications

(158 citation statements)

References 54 publications

(122 reference statements)

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“…Notwithstanding the large phenotypic heterogeneity in MDS, it is still unclear whether the onset of sAML is triggered by a single mutation or epigenetic event, or by an accumulation of multiple events. Some authors argue that one genetic event is sufficient for causing sAML [6][7][8] whereas others believe that several genetic events are required for the transformation [9,10]. The latest report on deep sequencing of the genome in patients with MDS before and after transformation to sAML [11] demonstrates complex clonal evolution with acquisition of multiple additional mutations, co-existing with the MDS founding clone.…”

Section: Introductionmentioning

confidence: 99%

Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database

et al. 2012

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One‐third of patients with myelodysplastic syndrome (MDS) progress to secondary acute myeloid leukemia (sAML), with its concomitant poor prognosis. Recently, multiple mutations have been identified in association with MDS‐to‐sAMLtransition, but it is still unclear whether all these mutations are necessary for transformation. If multiple independent mutations are required for the transformation, sAML risk should increase with time from MDS diagnosis. In contrast, if a single critical biological event determines sAML transformation; its risk should be constant in time elapsing from MDS diagnosis. To elucidate this question, we studied a database of 1079 patients with MDS. We classified patients according to the International Prognostic Scoring System (IPSS), using either the French‐American‐British (FAB) or the World Health Organization (WHO) criteria, and statistically analyzed the resulting transformation risk curves of each group. The risk of transformation after MDS diagnosis remained constant in time within three out of four risk groups, and in all four risk groups, when patients were classified according to FAB or to the WHO‐determined criteria, respectively. Further subdivision by blast percentage or cytogenetics had no influence on this result. Our analysis suggests that a single random biological event leads to transformation to sAML, thus calling for the exclusion of time since MDS diagnosis from the clinical decision‐making process. Am. J. Hematol. © 2012 Wiley Periodicals, Inc.

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Section: Introductionmentioning

confidence: 99%

Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database

et al. 2012

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“…Retroviruses were generated by transient transfection of Plat-E packaging cells with FuGene 6 (Roche Diagnostics, Mannheim, Germany), as described earlier. [18][19][20] …”

Section: Retroviral Constructs Transfection and Retrovirus Productionmentioning

confidence: 99%

“…20 C57BL/6 CD45.1 or CD45.2 mice were used as donors or recipients, respectively. Infected cells (2 Â 10 5 ) were intravenously injected into recipient mice, which had been administered a sublethal dose of g-irradiation.…”

Section: Mouse Bmtmentioning

confidence: 99%

“…Western blotting was performed as described. 20 Anti-AID mAb raised against the N-terminus of mAID, and anti-a-tubulin Ab (T6074, Sigma-Aldrich, St Louis, MO, USA) were used.…”

Section: Western Blottingmentioning

confidence: 99%

“…20 Flow cytometric analysis was performed with a FACSCalibur equipped with CellQuest software (BD Biosciences, San Jose, CA, USA) and Flowjo software (Tree Star, San Carlos, CA, USA).…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

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AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model

et al. 2010

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Molecular Genetics of Myelodysplastic Syndromes

Bejar

Steensma

2012

Encyclopedia of Life Sciences

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Myelodysplastic syndromes (MDS) are a group of clonal haematopoietic disorders characterised clinically by inefficient haematopoiesis, cytopenias of the peripheral blood and a risk of progression to acute myeloid leukaemia (AML). Molecularly, MDS can be associated with a wide range of acquired chromosomal abnormalities, epigenetic alterations and single gene mutations. These abnormalities affect diverse molecular pathways including ribonucleic acid (RNA) splicing machinery, epigenetic modifiers, haematopoietic transcription factors, receptor tyrosine kinase signalling, cell cycle regulation and apoptosis. The particular combination of somatic genetic lesions in any given patient will influence how their disease is manifested, and together with individual background germline genotype may explain much of the clinical heterogeneity associated with MDS. Here, the common genetic abnormalities that underlie MDS and how these abnormalities influence the development and progression of these disorders have been reviewed. Key Concepts: MDS represent a collection of disorders marked by abnormal, inefficient haematopoiesis, cytopenias of the peripheral blood and a predisposition for progression to AML. Like other haematopoietic malignancies, MDS arise from the clonal expansion of a single, abnormal haematopoietic cell. The abnormal MDS cells that maintain the disease have the ability to self‐renew and clonally expand because they have a selective growth advantage compared to their normal counterparts. Impaired haematopoietic differentiation in MDS can lead to cytopenias or to the production of terminally differentiated cells with abnormal function. A combination of somatic genetic abnormalities (acquired changes to the deoxyribonucleic acid (DNA) coding sequence), epigenetic abnormalities (heritable changes in gene expression) and marrow microenvironmental abnormalities contribute to the development and progression of MDS. Approximately, 50% of MDS cells have a chromosomal abnormality detectable by routine metaphase karyotype analysis. More than 75% of patients have acquired mutations in one or more genes known to be recurrently altered in MDS. Recurrent mutations in MDS implicate several molecular pathways in the development and progression of disease including; altered RNA splicing mechanisms, epigenetic changes in DNA methylation and histone modifications, activation of growth factor signalling cascades, impaired differentiation and abnormal regulation of cell cycle and apoptosis. Acquired mutations in several MDS genes have prognostic significance that is independent of clinically based prognostic scoring systems. Chromosomal abnormalities and mutations in some genes can predict response to specific therapies used to treat patients with MDS.

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AML1 mutations induced MDS and MDS/AML in a mouse BMT model

Cited by 143 publications

References 54 publications

Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database

Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database

AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model

Molecular Genetics of Myelodysplastic Syndromes

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