Reimagining AML and MDS: Exploring the Role of MDM2

The Spectrum of Myeloid Disorders

Myelodysplastic syndromes (MDS) are part of a spectrum of myeloid disorders, ranging from CHIP to secondary acute myeloid leukemia (AML). Moving along the spectrum, lower risk-MDS typically starts with inflammation. As inflammation increases, the disease may progress to higher-risk MDS and AML. These demonstrate further immune dysregulation, dysplasia and cytopenia, driven by persistent inflammation and genetic mutations.1-7

The Role of p53 and MDM2 in AML

Deficiency in the activity of p53, a crucial tumor suppressor protein, is known to drive many types of cancer, including AML.8,9 One key mechanism causing p53 deficiency is the overexpression of MDM2, which ubiquitinates p53 and targets it for degradation.9-11

 

Acronyms: AML = acute myeloid leukemia; CHIP = clonal hematopoeisis of indeterminate potential; CCUS = clonal cytopenia of undetermined significance; HR = high risk; LR = low risk; MDM2 = mouse double minute 2 homolog; MDS = myelodysplastic syndromes; p53 = p53 tumor suppressor protein.

 

References: 1. Bejar R. Best Pract Res Clin Haematol. 2018;31(4):341-345. doi:10.1016/j.beha.2018.10.002. 2. Steensma DP, Bejar R, Jaiswal S, et al. Blood. 2015;126(1):9-16. doi:10.1182/blood-2015-03-631747. 3. Attar EC. Harrison’s Manual of Oncology. 2nd ed. New York, NY: McGraw-Hill Education; 2014. 4. Kittang AO, Kordasti S, Sand KE, et al. Oncoimmunology. 2015;5(2):e1062208. doi:10.1080/2162402X.2015.1062208. 5. Gañán-Gómez I, Wei Y, Starczynowski DT, et al. Leukemia. 2015;29(7):1458-1469. doi:10.1038/leu.2015.69. 6. Chen X, Eksioglu EA, Zhou J, et al. J Clin Invest. 2013;123(11):4595-4611. doi:10.1172/JCI67580. 7. Epling-Burnette PK, Bai F, Painter JS, et al. Blood. 2007;109(11):4816-4824. doi:10.1182/blood-2006-07-035519. 8. Hainaut P. In: Hainaut P, Olivier M, Wiman KG, eds. p53 in the Clinics. New York, NY: Springer: 2013:1-23. 9. Quintas-Cardama A, Hu C, Qutub A, et al. Leukemia. 2017;31(6):1296-1305. doi:10.1038/leu.2016.350. 10. Haupt Y, Maya R, Kazaz A, Oren M. Nature. 1997;387(6630):296-299. doi: 10.1038/387296a0. 11. Chinnam M, Xu C, Lama R, et al. PLoS Genet. 2022;18(5):e1010171. doi:10.1371/journal.pgen.1010171.