TP53 突变型骨髓增生异常综合征/急性髓系白血病的骨髓微环境病理生物学与治疗机会

Mutations in TP53 inhibit p53 protective behaviors including cell cycle arrest, DNA damage repair protein recruitment, and apoptosis. The ubiquity of p53 in genome-stabilizing functions leads to an aberrant tumor microenvironment in TP53 -mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Profound immunosuppression mediated by myeloid-derived suppressor cells, the upregulation of cytokines and cell-surface receptors on leukemic cells, the suppression of native immune regulator cells, and metabolic aberrations in the bone marrow are features of the TP53 -mutated AML/MDS marrow microenvironment. These localized changes in the bone marrow microenvironment (BMME) explain why traditional therapies for MDS/AML, including chemotherapeutics and hypomethylating agents, are not as effective in TP53 -mutated myeloid neoplasms and demonstrate the dire need for new treatments in this patient population.

The unique pathophysiology of TP53 -mutated disease also provides new therapeutic approaches which are being studied, including intracellular targets (MDM2, p53), cell-surface protein biologics (immune checkpoint inhibitors, BiTE therapy, and antibody-drug conjugates), cell therapies (CAR-T, NK-cell), signal transduction pathways (Hedgehog, Wnt, NF- B, CCRL2, and HIF-1 ), and co-opted biologic pathways (cholesterol synthesis and glycolysis).

In this review, we will discuss the pathophysiologic anomalies of the tumor microenvironment in TP53 -mutant MDS/AML, the hypothesized mechanisms of chemoresistance it imparts, and how novel therapies are leveraging diverse therapeutic targets to address this critical area of need.