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Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.

Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS, Lamprecht TL, Shen D, Hundal J, Fulton RS, Heath S, Baty JD, Klco JM, Ding L, Mardis ER, Westervelt P, DiPersio JF, Walter MJ, Graubert TA, Ley TJ, Druley TE, Link DC, Wilson RK - Nature (2014)

Bottom Line: We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy.Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals.Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stem/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.

ABSTRACT
Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML and de novo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stem/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induce TP53 mutations. Rather, they support a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition of TP53 mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS.

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Model of how cytotoxic therapy shapes clonal evolution in t-AML/t-MDSAge-related mutations in hematopoietic stem/progenitor cells (HSPCs) result in the production of a genetically heterogeneous population of HSPCs, including rare HSPCs with heterozygous TP53 mutations in some individuals. During chemotherapy and/or radiotherapy for the primary cancer, HSPC clones harboring a TP53 mutation have a selective growth advantage, resulting in expansion of that clone. Subsequent acquisition of additional driver mutations results in transformation to t-AML/t-MDS. Of note, the presence of TP53 mutations likely accounts for this high incidence of cytogenetic abnormalities in t-AML/t-MDS and poor response to chemotherapy.
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Figure 7: Model of how cytotoxic therapy shapes clonal evolution in t-AML/t-MDSAge-related mutations in hematopoietic stem/progenitor cells (HSPCs) result in the production of a genetically heterogeneous population of HSPCs, including rare HSPCs with heterozygous TP53 mutations in some individuals. During chemotherapy and/or radiotherapy for the primary cancer, HSPC clones harboring a TP53 mutation have a selective growth advantage, resulting in expansion of that clone. Subsequent acquisition of additional driver mutations results in transformation to t-AML/t-MDS. Of note, the presence of TP53 mutations likely accounts for this high incidence of cytogenetic abnormalities in t-AML/t-MDS and poor response to chemotherapy.

Mentions: TP53 is the most commonly mutated gene in t-AML/t-MDS with 33.3% of patients affected in our series (Fig. 1g–h); the vast majority of these mutations have previously been identified as pathogenic10. Multivariate analysis revealed that TP53 mutations were associated with poor risk cytogenetics and a worse prognosis (Suppl. Tables 6 & 7 and Extended Data Fig. 2), both hallmarks of t-AML/t-MDS. These observations suggest a central role for TP53 mutations in the pathogenesis of many cases of t-AML/t-MDS. However, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unclear. The mutation burden in the genomic region containing TP53 (including silent Tier 1, Tier2, and Tier 3 mutations) is similar between t-AML and de novo AML (Extended Fig. 1C). Thus, it is not likely that chemotherapy directly induces TP53 mutations. We recently reported that individual HSPCs accumulate somatic mutations as a function of age, such that by age 50, there are on average 5 coding gene mutations per HSPC11. Based on this data and on current estimates that there are approximately 10,000 HSCs in humans12, we predict that 44% of healthy individuals at 50 years of age may have at least one HSPC that carries a randomly generated, functional TP53 mutation (see extended Methods). TP53 plays a central role in regulating cellular responses to genotoxic stress13–17, and loss of TP53 provides a selective advantage for neoplastic growth18. Together, these observations suggest a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment (Extended Data Fig. 3).


Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.

Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS, Lamprecht TL, Shen D, Hundal J, Fulton RS, Heath S, Baty JD, Klco JM, Ding L, Mardis ER, Westervelt P, DiPersio JF, Walter MJ, Graubert TA, Ley TJ, Druley TE, Link DC, Wilson RK - Nature (2014)

Model of how cytotoxic therapy shapes clonal evolution in t-AML/t-MDSAge-related mutations in hematopoietic stem/progenitor cells (HSPCs) result in the production of a genetically heterogeneous population of HSPCs, including rare HSPCs with heterozygous TP53 mutations in some individuals. During chemotherapy and/or radiotherapy for the primary cancer, HSPC clones harboring a TP53 mutation have a selective growth advantage, resulting in expansion of that clone. Subsequent acquisition of additional driver mutations results in transformation to t-AML/t-MDS. Of note, the presence of TP53 mutations likely accounts for this high incidence of cytogenetic abnormalities in t-AML/t-MDS and poor response to chemotherapy.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403236&req=5

Figure 7: Model of how cytotoxic therapy shapes clonal evolution in t-AML/t-MDSAge-related mutations in hematopoietic stem/progenitor cells (HSPCs) result in the production of a genetically heterogeneous population of HSPCs, including rare HSPCs with heterozygous TP53 mutations in some individuals. During chemotherapy and/or radiotherapy for the primary cancer, HSPC clones harboring a TP53 mutation have a selective growth advantage, resulting in expansion of that clone. Subsequent acquisition of additional driver mutations results in transformation to t-AML/t-MDS. Of note, the presence of TP53 mutations likely accounts for this high incidence of cytogenetic abnormalities in t-AML/t-MDS and poor response to chemotherapy.
Mentions: TP53 is the most commonly mutated gene in t-AML/t-MDS with 33.3% of patients affected in our series (Fig. 1g–h); the vast majority of these mutations have previously been identified as pathogenic10. Multivariate analysis revealed that TP53 mutations were associated with poor risk cytogenetics and a worse prognosis (Suppl. Tables 6 & 7 and Extended Data Fig. 2), both hallmarks of t-AML/t-MDS. These observations suggest a central role for TP53 mutations in the pathogenesis of many cases of t-AML/t-MDS. However, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unclear. The mutation burden in the genomic region containing TP53 (including silent Tier 1, Tier2, and Tier 3 mutations) is similar between t-AML and de novo AML (Extended Fig. 1C). Thus, it is not likely that chemotherapy directly induces TP53 mutations. We recently reported that individual HSPCs accumulate somatic mutations as a function of age, such that by age 50, there are on average 5 coding gene mutations per HSPC11. Based on this data and on current estimates that there are approximately 10,000 HSCs in humans12, we predict that 44% of healthy individuals at 50 years of age may have at least one HSPC that carries a randomly generated, functional TP53 mutation (see extended Methods). TP53 plays a central role in regulating cellular responses to genotoxic stress13–17, and loss of TP53 provides a selective advantage for neoplastic growth18. Together, these observations suggest a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment (Extended Data Fig. 3).

Bottom Line: We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy.Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals.Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stem/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.

ABSTRACT
Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML and de novo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stem/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induce TP53 mutations. Rather, they support a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition of TP53 mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS.

Show MeSH
Related in: MedlinePlus