Clinical implications of subclonal <i>TP53</i> mutations in acute myeloid leukemia

Prochazka, Katharina; Pregartner, Gudrun; Rücker, Frank G.; Heitzer, Ellen; Pabst, Gabriel; Wölfler, Albert; Zebisch, Armin; Berghold, Andrea; Döhner, Konstanze; Sill, Heinz

doi:10.3324/haematol.2018.205013

Cited by 72 publications

(93 citation statements)

References 38 publications

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“…According to the cytogenetic analysis, a sufficient number of metaphases was obtained in 84/98 (86%) patients showing a complex karyotype in 77 (92%) of them. The median VAF of the 108 TP53 mutations detected in this cohort was 48.7% (range, 4.7% to 97%); concurrent gene mutations were reported previously [41]. The median follow-up of patients with wild type TP53 AML (n = 1439) was 895 days, and of patients showing TP53 mutations-195 days, respectively.…”

Section: Resultssupporting

confidence: 60%

“…Most importantly, AML patients with TP53 mutations show resistance to intensive treatment strategies, including allogeneic hematopoietic stem cell transplantation (HSCT) with 3-year overall survival rates between 0% and 15% [38][39][40]. Recently, a dismal outcome has also been described when TP53 mutations occur in leukemic subclones with a variant allele frequency (VAF) of less than 20% [41].…”

Section: Introductionmentioning

confidence: 99%

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Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Dutta

Pregartner

Rücker

et al. 2020

Cancers

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Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this issue by analyzing data of 1537 patients intensively treated within protocols of the German-Austrian AML study group. We classified TP53 mutations depending on their impact on protein structure and according to the evolutionary action (EAp53) score and the relative fitness score (RFS). In 98/1537 (6.4%) patients, 108 TP53 mutations were detected. While the discrimination depending on the protein structure and the EAp53 score did not show a survival difference, patients with low-risk and high-risk AML-specific RFS showed a different overall survival (OS; median, 12.9 versus 5.5 months, p = 0.017) and event-free survival (EFS; median, 7.3 versus 5.2 months, p = 0.054). In multivariable analyses adjusting for age, gender, white blood cell count, cytogenetic risk, type of AML, and TP53 variant allele frequency, these differences were statistically significant for both OS (HR, 2.14; 95% CI, 1.15–4.0; p = 0.017) and EFS (HR, 1.97; 95% CI, 1.06–3.69; p = 0.033). We conclude that the AML-specific RFS is of prognostic value in patients with TP53-mutated AML and a useful tool for therapeutic decision-making.

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Section: Resultssupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Dutta

Pregartner

Rücker

et al. 2020

Cancers

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“…However, in therapy-related AML and in those with complex karyotype, the rate of TP53 mutations or deletions increases dramatically (approximately 70%) [140,141]. TP53 mutations are associated with resistance to chemotherapy, poor OS and poor disease-free survival (DFS) [142,143]. The sharp association with complex karyotype confirms TP53 as a pivotal guard of genome stability [144,145].…”

Section: Tp53 Mutationsmentioning

confidence: 99%

“…TP53 is also involved in the regulation of stem cell quiescence and self-renewal by directly interacting with telomerase [146]. Thus, the malignant clone may benefit from the presence of a TP53 mutated form that accelerates the ability of leukemia stem cells to proliferate after therapy, to accumulate mutations and to become resistant [142,143]. The vast majority of TP53 mutations occur in the region encoding the DNA-binding domain.…”

Section: Tp53 Mutationsmentioning

confidence: 99%

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

Panuzzo

Signorino

Calabrese

et al. 2020

JCM

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Acute myeloid leukemia is mainly characterized by a complex and dynamic genomic instability. Next-generation sequencing has significantly improved the ability of diagnostic research to molecularly characterize and stratify patients. This detailed outcome allowed the discovery of new therapeutic targets and predictive biomarkers, which led to develop novel compounds (e.g., IDH 1 and 2 inhibitors), nowadays commonly used for the treatment of adult relapsed or refractory AML. In this review we summarize the most relevant mutations affecting tumor suppressor genes that contribute to the onset and progression of AML pathology. Epigenetic modifications (TET2, IDH1 and IDH2, DNMT3A, ASXL1, WT1, EZH2), DNA repair dysregulation (TP53, NPM1), cell cycle inhibition and deficiency in differentiation (NPM1, CEBPA, TP53 and GATA2) as a consequence of somatic mutations come out as key elements in acute myeloid leukemia and may contribute to relapse and resistance to therapies. Moreover, spliceosomal machinery mutations identified in the last years, even if in a small cohort of acute myeloid leukemia patients, suggested a new opportunity to exploit therapeutically. Targeting these cellular markers will be the main challenge in the near future in an attempt to eradicate leukemia stem cells.

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“…One of the reasons is the genetic heterogeneity of AML with the majority of patients exhibiting distinct mutational subclones and diverse biological characteristics [1,2]. TP53 mutated AMLs are frequently resistant to intensive treatments and we recently showed that subclonal TP53 mutations confer an equally devastating prognosis [3]. This observation lead us to hypothesize that TP53 mutated subclones display characteristics of leukemic stem cells (LSCs) thus contributing to relapse or resistant disease.…”

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TP53 mutated AML subclones exhibit engraftment in a humanized bone marrow ossicle mouse model

et al. 2020

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Dear Editor,Despite extensive efforts to develop novel therapies, the prognosis of patients with acute myeloid leukemia (AML) is still poor. One of the reasons is the genetic heterogeneity of AML with the majority of patients exhibiting distinct mutational subclones and diverse biological characteristics [1,2]. TP53 mutated AMLs are frequently resistant to intensive treatments and we recently showed that subclonal TP53 mutations confer an equally devastating prognosis [3]. This observation lead us to hypothesize that TP53 mutated subclones display characteristics of leukemic stem cells (LSCs) thus contributing to relapse or resistant disease. We, therefore, tested LSC properties of these subclones in a recently developed, highly sensitive humanized bone marrow (BM) ossicle xenotransplantation mouse model [4,5].Patient specimens, experimental methods, and ethical approvals are described in detail in the Supplementary Data. Briefly, BM-derived mesenchymal stromal cells (MSCs) from healthy donors were expanded in vitro and subcutaneously injected into four sites of immunodeficient NOD/SCID/γ null (NSG) mice. These MSCs underwent endochondral ossification leading to the formation of a humanized BM ossicle microenvironment. We transplanted three diagnostic, T cell depleted AML specimens into ossicle-bearing NSG mice either by tail vein or direct intraossicle injection. Two specimens showed subclonal TP53 mutations with a variant allele frequency (VAF) of <20%, one a clonal TP53 mutation serving as control ( Supplementary Table 1). Mice were sacrificed 16-18 weeks post transplantation and humanized ossicles as well as mouse BM were analyzed for the engraftment of human leukemia. Leukemia engraftment was analyzed by multicolor flow cytometry, and different engrafted cell populations were sorted based on the expression of hCD45, hCD33 and hCD19 ( Supplementary Fig. 1). gDNA of sorted cells was analyzed for patient-specific TP53 and cooperating mutations using high-resolution mutation profiling allowing for the detection of mutations with a VAF of <0.1% [6].All three AML specimens showed engraftment in humanized ossicles as well as mouse BM. However, human cells preferentially engrafted in the humanized ossicle microenvironment ( Fig. 1a, Supplementary Fig. 2). For both AML samples with subclonal TP53 mutations, CD33+ leukemic cells constituted the predominant cell population within the graft. Interestingly, differentiation into CD19+ B-lymphoid cells was also observed and the subclonal TP53 mutations could be detected in both, the engrafted myeloid and lymphoid compartments (Figs. 1b, c; Supplementary Figs. 3,4; Supplementary Tables 2,3). These data indicate that subclones with TP53 mutations reveal characteristics of LSCs and pre-leukemic hematopoietic stem cells (pHSCs) being in line with our previous report on clonal TP53 mutations in AML [7]. Stem cell features may contribute to the fact that AML patients with subclonal TP53 mutations do also face an adverse prognosis since LSCs and pHSCs are considered less vulnerab...

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Clinical implications of subclonal TP53 mutations in acute myeloid leukemia

Cited by 72 publications

References 38 publications

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

TP53 mutated AML subclones exhibit engraftment in a humanized bone marrow ossicle mouse model

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