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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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Clonal evolution in case 314666a, Clinical course of case 341666. b, Unique adaptor sequencing was performed on genomic DNA derived from a leukapharesis samples obtained 3 years prior to the diagnosis of t-MDS for the two clonal mutations present in the diagnostic t-AML sample. Genomic DNA from a patient lacking these variants was used as a control. The blue circle indicates the position of the variant SNV. c, Proposed model of clonal evolution to t-MDS in this case.
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Figure 9: Clonal evolution in case 314666a, Clinical course of case 341666. b, Unique adaptor sequencing was performed on genomic DNA derived from a leukapharesis samples obtained 3 years prior to the diagnosis of t-MDS for the two clonal mutations present in the diagnostic t-AML sample. Genomic DNA from a patient lacking these variants was used as a control. The blue circle indicates the position of the variant SNV. c, Proposed model of clonal evolution to t-MDS in this case.

Mentions: The specific TP53 mutation present in the diagnostic t-AML/t-MDS sample was identified in prior-banked specimens in four out of the seven cases tested (see Supplementary Materials for case presentations); in the other three cases, we were unable to detect the diagnostic TP53 mutation in the prior banked blood or bone marrow sample; it is not clear whether these mutations were present but below our limit of detection or were truly absent. Patient 530447 developed t-AML after an autologous stem cell transplant for refractory Hodgkin's lymphoma (Fig. 2A). The diagnostic t-AML sample carried biallelic mutations of TP53, missense mutations of TET2 and NUP98, a silent mutation of CSMD1, and a subclonal KRAS mutation. Analysis of a leukapheresis sample obtained 6 years prior to the development of t-AML revealed that both TP53 mutant alleles were present with a variant allele fraction (VAF) of approximately 0.5% (Fig. 2b). The CSMD1 mutation was also present at the same VAF and is likely a passenger mutation. However, two potential driver mutations (TET2 and NUP98) were not detectable in the prior banked sample. Thus, these data show that, in this patient, the biallelic TP53 mutations preceded the development of t-AML by at least six years and antedated the development of the TET2 and NUP98 mutations (Fig. 2c). In a second case (patient 341666), a heterozygous R196* TP53 mutation was identified in mobilized peripheral blood leukocytes 3 years prior to the development of t-MDS at a frequency of 0.1%, preceding the acquisition of a RUNX1 mutation (Extended Data Fig. 5).


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)

Clonal evolution in case 314666a, Clinical course of case 341666. b, Unique adaptor sequencing was performed on genomic DNA derived from a leukapharesis samples obtained 3 years prior to the diagnosis of t-MDS for the two clonal mutations present in the diagnostic t-AML sample. Genomic DNA from a patient lacking these variants was used as a control. The blue circle indicates the position of the variant SNV. c, Proposed model of clonal evolution to t-MDS in this case.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

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

Figure 9: Clonal evolution in case 314666a, Clinical course of case 341666. b, Unique adaptor sequencing was performed on genomic DNA derived from a leukapharesis samples obtained 3 years prior to the diagnosis of t-MDS for the two clonal mutations present in the diagnostic t-AML sample. Genomic DNA from a patient lacking these variants was used as a control. The blue circle indicates the position of the variant SNV. c, Proposed model of clonal evolution to t-MDS in this case.
Mentions: The specific TP53 mutation present in the diagnostic t-AML/t-MDS sample was identified in prior-banked specimens in four out of the seven cases tested (see Supplementary Materials for case presentations); in the other three cases, we were unable to detect the diagnostic TP53 mutation in the prior banked blood or bone marrow sample; it is not clear whether these mutations were present but below our limit of detection or were truly absent. Patient 530447 developed t-AML after an autologous stem cell transplant for refractory Hodgkin's lymphoma (Fig. 2A). The diagnostic t-AML sample carried biallelic mutations of TP53, missense mutations of TET2 and NUP98, a silent mutation of CSMD1, and a subclonal KRAS mutation. Analysis of a leukapheresis sample obtained 6 years prior to the development of t-AML revealed that both TP53 mutant alleles were present with a variant allele fraction (VAF) of approximately 0.5% (Fig. 2b). The CSMD1 mutation was also present at the same VAF and is likely a passenger mutation. However, two potential driver mutations (TET2 and NUP98) were not detectable in the prior banked sample. Thus, these data show that, in this patient, the biallelic TP53 mutations preceded the development of t-AML by at least six years and antedated the development of the TET2 and NUP98 mutations (Fig. 2c). In a second case (patient 341666), a heterozygous R196* TP53 mutation was identified in mobilized peripheral blood leukocytes 3 years prior to the development of t-MDS at a frequency of 0.1%, preceding the acquisition of a RUNX1 mutation (Extended Data Fig. 5).

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