Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice

Abstract

• Egr1 haploinsufficiency in cooperation with reduced Tp53 activity accelerates the development of hematologic disease in mice.• Loss of 1 copy of Egr1 and Apc in hematopoietic stem cells, in cooperation with Tp53 loss, results in myeloid neoplasms.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. (Blood. 2014;123(7):1069-1078)

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

“…10 Deletion of 17p, to which TP53 is mapped, occurs in AML as a single aberration or with additional chromosomal abnormalities, indicating an unfavorable cytogenetic category. 2,59 The detrimental effect of 17p 2 is implicated to reflect a joined impact of TP53 loss and the reduced dosage of linked tumor suppressor genes.…”

“…[3][4][5][6][7][8][9][10] Currently, TP53 mutations, per se, are prioritized over other p53 abnormalities with regard to AML pathogenesis, therapy response, and prognosis. However, evolvement in the field of p53 research has modified our view of p53 dysfunction by elucidating the mutant p53 (mutp53) gain-of-function (GOF) phenomenon 11 and by unveiling molecular mechanisms underlying nonmutational wtp53 inactivation.…”

Retroviral insertional mutagenesis identifies the del(5q) genes, CXXC5, TIFAB and ETF1, as well as the Wnt pathway, as potential targets in del(5q) myeloid neoplasms

“…EGR1, a transcriptional regulator expressed at haploinsufficient levels in del(5q) t-MN patients, is involved in the homeostasis of hematopoietic stem cells, in myeloid differentiation, and in neoplastic transformation. 4,14 We hypothesize that dosage-dependent deregulation of hematopoietic transcriptional programs contributes to the development of myeloid disease; however, the affected Egr1 targets genes are still not known. Interestingly, there was a significant enrichment of provirally-targeted genes that contain binding sites for at least one or more haematologica 2016; 101:e234 LETTERS TO THE EDITOR Figure 3.…”

The progress of early growth response factor 1 and leukemia

“…It has been proven that loss of a single allele of more than one gene on 5q contributes to the pathogenesis of AML (69)(70)(71). A number of genes and several microRNAs (miRNAs) located on 5q, including miRNA-145, miRNA-146a, the ribosomal protein S14 (RPS14), the cell division cycle 25 (CDC25), the adenomatous polyposis coli gene (APC) have been implicated in the development of myeloid disorders caused by a gene dosage effect (72,73). (Figure 1) EGR1 may play a functional role in the pathogenesis of AML in patients with del(5q) (74,75).…”