Ppm1d truncating mutations promote the development of genotoxic stress-induced AML

Abstract

Hematopoietic stem cells (HSCs) ensure blood cell production during the life-time of an organism, and to do so they need to balance self-renewal, proliferation, differentiation, and migration in a steady state as well as in response to stress or injury. Importantly, aberrant proliferation of HSCs leads to hematological malignancies, and thus, tight regulation by various tumor suppressor pathways, including p53, is essential. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and promotes cell survival upon induction of genotoxic stress. Truncating mutations in the last exon of PPM1D lead to the production of a stable, enzymatically active protein and are commonly associated with clonal hematopoiesis. Using a transgenic mouse model, we demonstrate that truncated PPM1D reduces self-renewal of HSCs in basal conditions but promotes the development of aggressive AML after exposure to ionizing radiation. Inhibition of PPM1D suppressed the colony growth of leukemic stem and progenitor cells carrying the truncated PPM1D, and remarkably, it provided protection against irradiation-induced cell growth. Altogether, we demonstrate that truncated PPM1D affects HSC maintenance, disrupts normal hematopoiesis, and that its inhibition could be beneficial in the context of therapy-induced AML.

Hematopoietic stem cell fate under the influence of Ser/Thr protein phosphatases

“…For example, the selective PPM1D inhibitor GSK2830371 suppressed the growth of p53-positive cancer cells in vitro and in animal models. 5 -7 In the present study, Lu and colleagues used a new PPM1B inhibitor (HN252), proved its efficiency in animal models, and elegantly validated its specificity in the Ppm1b CKO animals. 1 , 2 This tool will be invaluable for exploring the functions of PPM1B in several systems.…”

“… 3 In addition, loss of the nuclear PPM1D (also called WIP1) phosphatase caused mTORC-dependent expansion of the HSC compartment in Ppm1d -/- animals, whereas truncating gain-of-function mutations in PPM1D reduced self-renewal of HSC. 4 , 5 Interestingly, the truncated PPM1D stimulates HSC survival after genotoxic stress by inhibiting the p53 pathway and can promote therapy-induced acute myeloid leukemia. 5 , 6 Altogether, these observations point at the crucial role of Ser/Thr phosphatases in the regulation of HSC properties and their potential contribution to the development of hematologic disorders.…”

“… 4 , 5 Interestingly, the truncated PPM1D stimulates HSC survival after genotoxic stress by inhibiting the p53 pathway and can promote therapy-induced acute myeloid leukemia. 5 , 6 Altogether, these observations point at the crucial role of Ser/Thr phosphatases in the regulation of HSC properties and their potential contribution to the development of hematologic disorders. In fact, several phosphatases have been implicated in hematologic malignancies as well as in solid tumors, and may represent attractive pharmacological targets in future clinical interventions.…”

CHIP: a clonal odyssey of the bone marrow niche

“…The role of Ppm1d mutations in AML development was further corroborated in vivo. While a single dose of γ radiation or two doses of 5-fluorouracil (5-FU) delivered over two weeks failed to initiate leukemia development in Ppm1d mutant mice, sequential treatment with four doses of γ radiation over eight weeks induced eventual AML transformation in a proportion of Ppm1d -mutant mice ( 58 ). These data suggest that malignant transformation depends on cumulative exposures to genotoxic stressors.…”

Low-Frequency PPM1D Gene Mutations Affect Treatment Response to CD19-Targeted CAR T-Cell Therapy in Large B-Cell Lymphoma

“…Amplification and/or overexpression of PPM1D has been described in a significant number of solid tumors, suggesting a role for PPM1D in carcinogenesis [41][42][43][44]. In addition, studies have shown that the truncated protein products can lead to a relative fitness of hematopoietic cells in the presence of chemotherapy [34,[45][46][47].…”