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ACUTE MYELOID LEUKEMIA

PPM1D mutations appear in complete remission after exposure to chemotherapy without predicting emerging AML relapse

Leukemia volume 35, pages 2693–2697 (2021)Cite this article

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Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by the uncontrolled clonal expansion of undifferentiated myeloblasts [1, 2]. Hematopoietic clonal expansion is often the result of age-related acquisition of somatic driver mutations in hematopoietic stem or progenitor cells (HSPCs). In these conditions HSPCs acquire distinct sets of mutations [3], conferring fitness advantage and clonal expansion, ultimately leading to a genetically heterogeneous group of diseases [4,5,6]. Increased clonal expansion has been observed to occur subsequent to particular biologic conditions and cellular stressors, such as aplastic anemia [7] and cytotoxic therapy [8, 9], resulting in outgrowth of cells carrying specific subsets of mutations, i.e., in PIGA, BCOR, and BCORL1 in AA [7] and in TP53, CHEK2, and PPM1D [8, 9] after chemo- and radiotherapy. This observation suggests that cellular stressors affect clonal evolution toward the development of secondary malignancy or relapse. Recently, Wong et al. demonstrated that stress from cytotoxic therapy promotes the expansion of clones with mutations in DNA damage response (DDR) genes, such as protein phosphatase Mg2+/Mn2+ 1D (PPM1D) [10].

The PPM1D gene encodes a protein phosphatase that is upregulated in a p53-dependent manner in response to DNA damage. PPM1D regulates the DDR pathway through dephosphorylation of TP53 and other tumor suppressor target proteins [11]. PPM1D functions as an inhibitor or homeostatic regulator of the DDR by facilitating the return of cells into steady state following DNA damage [12, 13]. Mutations in the PPM1D gene have been found to occur in various malignancies, such as breast and ovarian cancers [14]. PPM1D mutations are also reported to be present in blood of healthy individual with no history of hematological malignancy; indicating that this gene drives clonal hematopoiesis [4]. In myeloid neoplasms, PPM1D mutations are more frequent in patients with therapy related than in de novo disorders [15]. Remarkably, virtually all PPM1D mutations are truncating variants that predominantly occur in exon 6 of PPM1D and are considered to be gain-of-function mutations that impair TP53 function [15, 16]. Recently, Kahn et al. showed that protein truncating PPM1D mutations result in a chemo resistance phenotype leading to expansion of PPM1D mutant cells under selective pressure, as a consequence of an altered DDR respons [16]. In vitro and in vivo expansion of PPM1D mutant clones in the presence of chemotherapy was reversible using PPM1D inhibitors [16].

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Fig. 1: Evolution of PPM1D and co-occuring mutations during treatment in AML patients with relapse.
Fig. 2: Evolution of PPM1D and co-occuring mutations during treatment in AML patients without relapse.

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Authors and Affiliations

  1. Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Adil S. A. Al Hinai, Tim Grob, Melissa Rijken, François G. Kavelaars, Annelieke Zeilemaker, Claudia A. J. Erpelinck-Verschueren, Mathijs A. Sanders, Bob Löwenberg, Mojca Jongen-Lavrencic & Peter J. M. Valk

  2. National Genetic Center, Ministry of Health, Muscat, Sultanate of Oman

    Adil S. A. Al Hinai

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Al Hinai, A.S.A., Grob, T., Rijken, M. et al. PPM1D mutations appear in complete remission after exposure to chemotherapy without predicting emerging AML relapse. Leukemia 35, 2693–2697 (2021). https://doi.org/10.1038/s41375-021-01155-y

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