Age-specific induction of mutant p53 drives clonal hematopoiesis and acute myeloid leukemia in adult mice.

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem cells (HSCs) collaborate with mutant p53 to predispose toward myeloid transformation rather than lymphoma development. Our study unveils new insights into the cooperative impact of HSC age, Trp53 mutations, and Mdm2 haploinsufficiency on clonal hematopoiesis and the development of myeloid malignancies.

Comparison of corneal tomographic parameters between Hispanic and non-Hispanic patients.

PURPOSE: To compare corneal tomographic parameters between Hispanic White and non-Hispanic White patients using Pentacam data. METHODS: This retrospective study evaluated preoperative Pentacam data from 641 patients 50 years or older who underwent surgery for senile cataract and self-identified as Hispanic or non-Hispanic White. Patients of non-White race or multiethnic groups, or a history of surgery, trauma, or any abnormality of the cornea or anterior segment were excluded. Cornea and anterior segment parameters, as measured with Pentacam, were then compared between Hispanics and non-Hispanics. RESULTS: There were 352 Hispanic White and 289 non-Hispanic White patients. These included 231 men and 410 women, with a mean age of 69.5 ± 8.2 years. There were no significant differences between Hispanics and non-Hispanics in front or back keratometry or amount of front astigmatism. However, Hispanics had a greater amount of back astigmatism (0.36 ± 0.19 vs 0.32 ± 0.17 diopter, P = 0.04). Moreover, there was a statistically significant difference in front steep axis of the left eyes between Hispanics and non-Hispanics (97.8 ± 47.9 vs 108.2 ± 48.9 deg, P = 0.01), and a marginally significant difference in front steep axis of the right eyes (81.0 ± 48.2 vs 73.5 ± 49.9 deg, P = 0.06). Hispanics also had a lower vertex pachymetry (548.1 ± 34.5 vs 553.4 ± 37.4 µm, P = 0.04) and a smaller anterior chamber volume (134.7 ± 39.0 vs 146.1 ± 39.9 mm3, P < 0.001). CONCLUSIONS: There are some differences in cornea and anterior segment parameters between Hispanics and non-Hispanics 50 years or older who underwent surgery for senile cataract. However, such differences may not be clinically significant.

Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias.

The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance.

Mdm2/p53 levels in bone marrow mesenchymal stromal cells is essential for maintaining the hematopoietic niche in response to DNA damage.

Mesenchymal stromal cells (MSCs) are a key component of the bone marrow (BM) niche, providing essential support required for maintenance of hematopoietic stem cells. To advance our understanding of physiological functions of p53 and Mdm2 in BM-MSCs, we developed traceable conditional mouse models targeting Mdm2 and/or Trp53 in vivo . We demonstrate that Mdm2 is essential for the emergence, maintenance and hematopoietic support of BM-MSCs. Mdm2 haploinsufficiency in BM-MSCs resulted in genotoxic stress-associated thrombocytopenia, suggesting a functional role for Mdm2 in hematopoiesis. In a syngeneic mouse model of acute myeloid leukemia (AML), Trp53 deletion in BM-MSCs improved survival, and protected BM against hematopoietic toxicity from a murine Mdm2i, DS-5272. The transcriptional changes were associated with dysregulation of glycolysis, gluconeogenesis, and Hif-1α in BM-MSCs. Our results reveal a physiologic function of Mdm2 in BM-MSC, identify a previously unknown role of p53 pathway in BM-MSC-mediated support in AML and expand our understanding of the mechanism of hematopoietic toxicity of MDM2is.

DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia.

Peposertib (M3814) is a potent and selective DNA-PK inhibitor in early clinical development. It effectively blocks non-homologous end-joining repair of DNA double-strand breaks (DSB) and strongly potentiates the antitumor effect of ionizing radiation (IR) and topoisomerase II inhibitors. By suppressing DNA-PK catalytic activity in the presence of DNA DSB, M3814 potentiates ATM/p53 signaling leading to enhanced p53-dependent antitumor activity in tumor cells. Here, we investigated the therapeutic potential of M3814 in combination with DSB-inducing agents in leukemia cells and a patient-derived tumor. We show that in the presence of IR or topoisomerase II inhibitors, M3814 boosts the ATM/p53 response in acute leukemia cells leading to the elevation of p53 protein levels as well as its transcriptional activity. M3814 synergistically sensitized p53 wild-type, but not p53-deficient, AML cells to killing by DSB-inducing agents via p53-dependent apoptosis involving both intrinsic and extrinsic effector pathways. The antileukemic effect was further potentiated by enhancing daunorubicin-induced myeloid cell differentiation. Further, combined with the fixed-ratio liposomal formulation of daunorubicin and cytarabine, CPX-351, M3814 enhanced the efficacy against leukemia cells in vitro and in vivo without increasing hematopoietic toxicity, suggesting that DNA-PK inhibition could offer a novel clinical strategy for harnessing the anticancer potential of p53 in AML therapy.