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

Abstract

The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices. (Blood. 2017; 130(6):699-712)

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery

“…Moreover, our data indicate that aneuploidy shapes the transcriptional profile of leukemic cells by affecting the expression of a set of genes, which is independent of the identity of the single chromosomes, as observed in aneuploid models. 27 We show here that the p53 transcriptional program is generally silenced in A-AML through either structural or functional inactivation, which can be mediated by a number of events, 46 including mutations of the p53 regulators SETD2, DDX31, USP10, and USP4, decreased expression of DMTF1 and HINT1, and increased levels of PRKCA. 38 Evidence is available in the literature for some genes, including BUB1B, 39 NSUN2, 40 ESPL1, 41 CDK5RAP2, 42 NDC1, 43 and USP44, 44 which are mutated in A-AML, and NPM1, 45 which is targeted by CN loss.…”

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

“…For example, some NPM1 mutations encode a mutant protein that causes cytoplasmic mislocalization and dysregulation of the MDM2 inhibitor and hence TP53 activator, ARF . FLT3‐ITD mutations also promote TP53 inactivation . In sum, although most de novo AML retain wild‐type TP53 , leukemic cells appear to gain the benefits of TP53 inactivation by other sources.…”

“…Although wild‐type TP53 acts as a tumor suppressor by activating downstream target genes, GOF are thought to mostly result from the binding of mutant TP53 to different proteins, including transcription factors . Among the cellular impacts of mutant TP53 GOF in AML are genomic destabilization, loss of cell‐cycle control, enhanced proliferation of tumor cells, and chemoresistance …”

“…Given the low frequency of TP53 mutations in AML, the reactivation of intact TP53 activity has risen as a promising therapeutic opportunity . The precise strategies to do so must take into account the means of TP53 pathway inactivation . Recent data indicate that most AML subsets may bear TP53 inactivation by different mechanisms, such as MDM2/MDMX upregulation, NPM1 and FLT3 mutations, fusion proteins ensuing chromosomal translocations, and aberrant expression of certain miRs …”

“…Indeed, alteration or loss of the TP53 locus encoding TP53 is one of the most powerful independent indicators of poor outcome in this disease ( Figure 2C). 8,15,16 In addition, TP53 mutations are more common in AML cases with increased genomic instability, such as therapy-related, relapsed, and elderly AML patients, as well as therapy-related myelodysplastic syndrome (t-MDS). [16][17][18][19][20][21][22][23] In therapy-related AML (t-AML) and t-MDS, often grouped together as therapy-related leukemia, TP53 mutations are present in~30% of patients ( Figure 2D).…”