PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy

Hsu, Joanne I.; Dayaram, Tajhal; Tovy, Ayala; Braekeleer, Étienne De; Jeong, Mira; Wang, Feng; Zhang, Jianhua; Heffernan, Timothy P.; Gera, Sonal; Kovacs, Jeffery; Marszalek, Joseph R.; Bristow, Christopher A.; Yan, Yuanqing; Garcia‐Manero, Guillermo; Kantarjian, Hagop M.; Vassiliou, George S.; Futreal, P. Andrew; Donehower, Lawrence A.; Takahashi, Koichi; Goodell, Margaret A.

doi:10.1016/j.stem.2018.10.004

Cited by 323 publications

(293 citation statements)

References 47 publications

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“…73 Similarly, human and murine hematopoietic cells with PPM1D mutations were shown to outcompete wild type cells after exposure to DNA-damaging agents. 74 Importantly, several studies now have shown that patients with CH and in particular CH-PD have significantly increased risks of developing myeloid neoplasia ( Figure 2C). Based on case-control studies, solid tumor patients with CH have an approximately 5-to 15-fold increased risk of developing t-MN.…”

Section: Ch and Risk Of Therapy-related Myeloid Malignanciesmentioning

confidence: 98%

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Hartmann

Metzeler

2019

Genes Chromosomes & Cancer

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Myeloid neoplasms including myelodysplastic syndromes and acute myeloid leukemia (AML) originate from hematopoietic stem cells through sequential acquisition of genetic and epigenetic alterations that ultimately cause the disease‐specific phenotype of impaired differentiation and increased proliferation. It has become clear that preleukemic clonal hematopoiesis (CH), characterized by an expansion of stem and progenitor cells that carry somatic mutations but are still capable of normal differentiation, can precede the development of clinically overt myeloid neoplasia by many years. CH commonly develops in the aging hematopoietic system, yet progression to myelodysplasia or AML is rare. The discovery that myeloid neoplasms frequently develop from premalignant precursor conditions that are detectable in many healthy individuals has important consequences for the diagnosis, and potentially for the treatment of these disorders. In this review, we summarize the current knowledge on CH as a precursor of myeloid cancers and the implications of CH‐related gene mutations in the diagnostic workup of patients with suspected myelodysplastic syndrome. We will discuss the risk of progression associated with CH in healthy persons and in patients undergoing chemotherapy for a non‐hematologic cancer, and the significance of CH in autologous and allogeneic stem cell transplantation. Finally, we will review the significance of preleukemic clones in AML and their persistence in patients who achieve a remission after chemotherapeutic treatment.

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Section: Ch and Risk Of Therapy-related Myeloid Malignanciesmentioning

confidence: 98%

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Hartmann

Metzeler

2019

Genes Chromosomes & Cancer

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“…Interestingly, early detection of CHIP may predict risk of developing cardiovascular disease, with potentially actionable consequences. As well, PPM1D mutations are common in solid tumor patients who have received platinum therapy and appear to predispose to a secondary hematological malignancy . Screening for these mutations may also be of clinical benefit.…”

Section: When Should Screening Occur?mentioning

confidence: 99%

“…As well, PPM1D mutations are common in solid tumor patients who have received platinum therapy and appear to predispose to a secondary hematological malignancy. 71 Screening for these mutations may also be of clinical benefit. Further research is needed to better define the risks and benefits of broad-based screening for clonal hematopoiesis.…”

Section: When S Hould Screening O Ccur?mentioning

confidence: 99%

Genomic testing in myeloid malignancy

Docking

Karsan

2019

Int J Lab Hematology

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Clinical genetic testing in the myeloid malignancies is undergoing a rapid transition from the era of cytogenetics and single‐gene testing to an era dominated by next‐generation sequencing (NGS). This transition promises to better reveal the genetic alterations underlying disease, but there are distinct risks and benefits associated with different NGS testing platforms. NGS offers the potential benefit of being able to survey alterations across a wider set of genes, but analytic and clinical challenges associated with incidental findings, germ line variation, turnaround time, and limits of detection must be addressed. Additionally, transcriptome‐based testing may offer several distinct benefits beyond traditional DNA‐based methods. In addition to testing at disease diagnosis, research indicates potential benefits of genetic testing both prior to disease onset and at remission. In this review, we discuss the transition from the era of cytogenetics and single‐gene tests to the era of NGS panels and genome‐wide sequencing—highlighting both the potential and drawbacks of these novel technologies.

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“…The very wide variation in VAFs observed between people is largely caused by the combined effects of chance (when a mutation arises) and fitness differences (how fast they expand). While cell-extrinsic effects are likely crucial in specific contexts such as chemotherapy 11,26,40,41 and acute infection 42,43 , the data from healthy individuals are quantitatively consistent with cell-intrinsic differences in fitness effects being the major determinants of the variation.…”

Section: A Simple Framework Explains Clonal Haematopoiesismentioning

confidence: 62%

The evolutionary dynamics and fitness landscape of clonal haematopoiesis

Watson

Papula

Poon

et al. 2019

Preprint

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Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance, however, remains largely unknown. Here, by combining blood sequencing data from ∼50,000 individuals, we reveal how mutation, genetic drift and fitness differences combine to shape the genetic diversity of healthy blood ('clonal haematopoiesis'). By analysing the spectrum of variant allele frequencies we quantify fitness advantages for key pathogenic variants and genes and provide bounds on the number of haematopoietic stem cells. Positive selection, not drift, is the major force shaping clonal haematopoiesis. The remarkably wide variation in variant allele frequencies observed across individuals is driven by chance differences in the timing of mutation acquisition combined with differences in the cell-intrinsic fitness effect of variants. Contrary to the widely held view that clonal haematopoiesis is driven by ageing-related alterations in the stem cell niche, the data are consistent with the age dependence being driven simply by continuing risk of mutations and subsequent clonal expansions that lead to increased detectability at older ages. clonal haematopoiesis | haematopoietic stem cells | evolution | population genetics | DNMT3A | TET2 | spliceosome | TP53 | acute myeloid leukaemia Correspondence: cw672@cam.ac.uk & jrb75@cam.ac.uk ResultsThe VAF distribution from ∼50,000 individuals. We analysed VAF measurements for somatic variants in the blood from ∼50,000 blood-cancer-free individuals from nine publicly available blood sequencing datasets 7-15 (Supplementary Information 1). VAF measurements in bone marrow and peripheral blood show good concordance 30 and so Watson | bioRχiv |

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PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy

Cited by 323 publications

References 47 publications

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Genomic testing in myeloid malignancy

The evolutionary dynamics and fitness landscape of clonal haematopoiesis

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