title: Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice.
abstract: An interstitial deletion of chromosome 5, del(5q), is the most common structural abnormality in primary myelodysplastic syndromes (MDS) and therapy-related myeloid neoplasms (t-MNs) after cytotoxic therapy. Loss of TP53 activity, through mutation or deletion, is highly associated with t-MNs with a del(5q). We previously demonstrated that haploinsufficiency of Egr1 and Apc, 2 genes lost in the 5q deletion, are key players in the progression of MDS with a del(5q). Using genetically engineered mice, we now show that reduction or loss of Tp53 expression, in combination with Egr1 haploinsufficiency, increased the rate of development of hematologic neoplasms and influenced the disease spectrum, but did not lead to overt myeloid leukemia, suggesting that altered function of additional gene(s) on 5q are likely required for myeloid leukemia development. Next, we demonstrated that cell intrinsic loss of Tp53 in hematopoietic stem and progenitor cells haploinsufficient for both Egr1 and Apc led to the development of acute myeloid leukemia (AML) in 17% of mice. The long latency (234-299 days) and clonal chromosomal abnormalities in the AMLs suggest that additional genetic changes may be required for full transformation. Thus, loss of Tp53 activity in cooperation with Egr1 and Apc haploinsufficiency creates an environment that is permissive for malignant transformation and the development of AML.
authors.affiliation: Department of Medicine and.
authors.forename: Angela
authors.initials: A
authors.lastname: Stoddart
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Fernald
authors.forename: Jianghong
authors.initials: J
authors.lastname: Wang
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Davis
authors.forename: Theodore
authors.initials: T
authors.lastname: Karrison
authors.forename: John
authors.initials: J
authors.lastname: Anastasi
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D002872:Chromosome Deletion; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D017353:Gene Deletion; D017491:Genes, APC; D016158:Genes, p53 / Q000502:physiology*; D057895:Haploinsufficiency; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse