Flt3-ITD mutations in a mouse model of radiation-induced acute myeloid leukaemia

Finnon, Rosemary; Brown, Natalie; Moody, J.C.; Badie, Christophe; Olme, C.-H.; Huiskamp, R.; Meijne, Emmy; Sutmuller, Marjolein; Rosemann, Michael; Bouffler, Simon

doi:10.1038/leu.2011.377

Cited by 23 publications

(22 citation statements)

References 7 publications

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“…Importantly, reduction to about 20% of normal levels of the gene or conditional complete inactivation in vivo were found to lead to the development of AML [21,22]. Some cases of rAML do not have Sfpi1 deletions or point mutations and recently we have reported internal tandem duplications in Flt3 (the most common mutation in human AML) within a panel of rAMLs [23]. An inverse relationship between the expression of the gene Flt3 and S fpi1 has also been observed [24,25].…”

Section: Introductionmentioning

confidence: 99%

Live cell detection of chromosome 2 deletion and Sfpi1/PU1 loss in radiation-induced mouse acute myeloid leukaemia

et al. 2013

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The CBA/H mouse model of radiation-induced acute myeloid leukaemia (rAML) has been studied for decades to bring to light the molecular mechanisms associated with multistage carcinogenesis. A specific interstitial deletion of chromosome 2 found in a high proportion of rAML is recognised as the initiating event. The deletion leads to the loss of Sfpi, a gene essential for haematopoietic development. Its product, the transcription factor PU.1 acts as a tumour suppressor in this model. Although the deletion can be detected early following ionising radiation exposure by cytogenetic techniques, precise characterisation of the haematopoietic cells carrying the deletion and the study of their fate in vivo cannot be achieved. Here, using a genetically engineered C57BL/6 mouse model expressing the GFP fluorescent molecule under the control of the Sfpi1 promoter, which we have bred onto the rAML-susceptible CBA/H strain, we demonstrate that GFP expression did not interfere with X-ray induced leukaemia incidence and that GFP fluorescence in live leukaemic cells is a surrogate marker of radiation-induced chromosome 2 deletions with or without point mutations on the remaining allele of the Sfpi1 gene. This study presents the first experimental evidence for the detection of this leukaemia initiating event in live leukemic cells.

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Section: Introductionmentioning

confidence: 99%

Live cell detection of chromosome 2 deletion and Sfpi1/PU1 loss in radiation-induced mouse acute myeloid leukaemia

et al. 2013

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“…, Flt3 cytokine receptor that are found in 25% of human AML) [81]. Interestingly, Finnon et al have recently shown that Flt3 -ITD and Sfpi 1/PU.1 mutations are mutually exclusive in murine radiation-induced AML without any overt phenotypic differences [97]. The group has not reported actual levels of PU.1 in these RI-AMLs, so it is plausible that the PU.1 depression is still involved in these malignancies.…”

Section: Resultsmentioning

confidence: 99%

Mouse Models for Efficacy Testing of Agents against Radiation Carcinogenesis — A Literature Review

Rivina

Schiestl

2012

IJERPH

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As the number of cancer survivors treated with radiation as a part of their therapy regimen is constantly increasing, so is concern about radiation-induced cancers. This increases the need for therapeutic and mitigating agents against secondary neoplasias. Development and efficacy testing of these agents requires not only extensive in vitro assessment, but also a set of reliable animal models of radiation-induced carcinogenesis. The laboratory mouse (Mus musculus) remains one of the best animal model systems for cancer research due to its molecular and physiological similarities to man, small size, ease of breeding in captivity and a fully sequenced genome. This work reviews relevant M. musculus inbred and F1 hybrid animal models and methodologies of induction of radiation-induced leukemia, thymic lymphoma, breast, and lung cancer in these models. Where available, the associated molecular pathologies are also included.

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“…Mutations in FLT3 kinase which are frequent in AML patients and were identified in radiation-induced mouse AML [3], affect the extracellular signal-regulated kinase ERK1/2 [23]. Sorcin (Sri) is highly expressed in the heart and in the brain, and overexpressed in many cancer cells in general and in AML [24].…”

Section: Discussionmentioning

confidence: 99%

“…Whether these two events are either necessary or sufficient for leukaemogenesis is not clear. There is at least one alternative pathway of leukaemogenesis in the mouse involving internal tandem duplication (ITD) mutations of Flt3 [3], indicating that direct Sfpi1 involvement is not necessary. Furthermore, some studies have suggested that point mutations are not rate limiting [4], possibly suggesting that Sfpi1 deletion and point mutation are not jointly sufficient.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic and proteomic analysis of mouse radiation-induced acute myeloid leukaemia (AML)

et al. 2016

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A combined transcriptome and proteome analysis of mouse radiation-induced AMLs using two primary AMLs, cell lines from these primaries, another cell line and its in vivo passage is reported. Compared to haematopoietic progenitor and stem cells (HPSC), over 5000 transcriptome alterations were identified, 2600 present in all materials. 55 and 3 alterations were detected in the proteomes of the cell lines and primary/in vivo passage material respectively, with one common to all materials. In cell lines, approximately 50% of the transcriptome changes are related to adaptation to cell culture, and in the proteome this proportion was higher. An AML ‘signature’ of 17 genes/proteins commonly deregulated in primary AMLs and cell lines compared to HPSCs was identified and validated using human AML transcriptome data. This also distinguishes primary AMLs from cell lines and includes proteins such as Coronin 1, pontin/RUVBL1 and Myeloperoxidase commonly implicated in human AML. C-Myc was identified as having a key role in radiation leukaemogenesis. These data identify novel candidates relevant to mouse radiation AML pathogenesis, and confirm that pathways of leukaemogenesis in the mouse and human share substantial commonality.

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Flt3-ITD mutations in a mouse model of radiation-induced acute myeloid leukaemia

Cited by 23 publications

References 7 publications

Live cell detection of chromosome 2 deletion and Sfpi1/PU1 loss in radiation-induced mouse acute myeloid leukaemia

Live cell detection of chromosome 2 deletion and Sfpi1/PU1 loss in radiation-induced mouse acute myeloid leukaemia

Mouse Models for Efficacy Testing of Agents against Radiation Carcinogenesis — A Literature Review

Transcriptomic and proteomic analysis of mouse radiation-induced acute myeloid leukaemia (AML)

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