Understanding and Targeting TP53 in Myeloid Malignancies
TP53 mutations are common in myeloid malignancies and associated with poor outcomes. Functional inactivation of wild-type TP53 also occurs frequently and contributes to disease pathogenesis. How leukemia cells with mutant or dysregulated TP53 persist and ultimately expand likely depends on several variables, including the type of mutation, the hematopoietic cell of origin, and the presence of hematopoietic cell-intrinsic and cell-extrinsic stressors. A better understanding of the interplay between these variables is necessary to develop therapeutic strategies and improve patient outcomes. This session will highlight the diverse biology of TP53 mutations on the pathogenesis of myeloid malignancies and the benefits and potential risks of targeting regulators of TP53 function in the clinic.
Dr. Scott Lowe will address how TP53 mutations are common in therapy-related myeloid neoplasia and complex karyotype acute myeloid leukemia (CK-AML), including how they are associated with chemoresistance and poor prognosis in AML. To understand the impact of TP53 mutations on AML biology, his group has performed large-scale genomic analyses of TP53 mutant AML and generated a series of animal models that faithfully reflect molecular and biological features of the human disease. Their recent studies explored the biology of particular TP53 mutational configurations that drive AML initiation and maintenance as well as characterized the events that cooperate with TP53 mutations during leukemogenesis.
Dr. Ulrich Steidl will discuss how TP53 is often inactivated by mutations or other mechanisms in human cancers. Recent work has demonstrated that its endogenous inhibitor MDMX (or MDM4) is frequently overexpressed in patients with hematologic malignancies including AML, as well as other cancers. Pharmacological disruption of the interactions of TP53 with both its endogenous inhibitors (MDMX and MDM2) has long been sought after as an attractive strategy to restore TP53-dependent tumor suppressor activity. However, selective targeting of this pathway has previously been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. More recently, pharmacological dual targeting of MDMX/MDM2 has become feasible through stapled peptides and is currently being tested in clinical trials. This presentation will discuss such MDMX/MDM2 dual-targeting strategies as well as new insights into MDMX-mediated mechanisms of tumor progression at the stem cell level, which have emerged from recent studies.
Dr. Veronika Sexl will discuss the role of the cyclin dependent kinase CDK6 as a transcriptional regulator controlling hematopoietic stem cell quiescence and leukemogenesis. Results from her laboratory have shown that CDK6 counteracts TP53 induced function during transformation by inducing a complex transcriptional response co-regulated by nuclear transcription factor Y subunit alpha and SP1. In murine models, CDK6 deficiency requires functional TRP53 inactivation to allow for transformation.
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