Abstract
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.
Highlights
Ionising radiation is a known leukaemogen, evidence from studies of the Japanese atomic bomb survivors indicate that acute myeloid leukaemia (AML) predominates [eg 1]
The experimental materials available (Figure 1) and results obtained allow for the identification of transcriptome and proteome changes associated with two primary leukaemias (RF12-p, RF26-p), three AML cell lines (RF12-cl, RF26-cl, MLP3-cl) and an in vivo passaged cell line (MLP3-ivp)
The primary AMLs and derived cell lines, RF12-p, RF26-p, RF12-cl and RF26cl were found to be hemizygous for Sfpi1 and carry point mutations in the retained allele such that the protein carried the R235C amino acid substitution
Summary
Ionising radiation is a known leukaemogen, evidence from studies of the Japanese atomic bomb survivors indicate that acute myeloid leukaemia (AML) predominates [eg 1]. The majority of mouse radiation-induced AMLs carry a deletion of one allele of the Sfpi gene, the mouse homologue of human PU., and accompanying point mutations at codon 235 in the retained allele of the gene. 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 Sfpi involvement is not necessary. Some studies have suggested that point mutations are not rate limiting [4], possibly suggesting that Sfpi deletion and point mutation are not jointly sufficient
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