Patients with therapy-related myelodysplastic syndromes and acute myeloid leukemia share genetic features but can be separated by blast counts and cytogenetic risk profiles into prognostically relevant subgroups

Bacher, Ulrike; Haferlach, Claudia; Alpermann, Tamara; Schnittger, Susanne; Kern, Wolfgang; Haferlach, Torsten

doi:10.3109/10428194.2012.717275

Cited by 12 publications

(8 citation statements)

References 8 publications

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“…Recent studies have shown that t-MDS with a low blast count is less aggressive than t-AML [7, 35]. In this study, we showed that the frequency of TP53 mutations were similarly high in both t-MDS and t-AML; however, mutations in genes other than TP53 were significantly higher in t-AML than t-MDS.…”

Section: Discussionsupporting

confidence: 46%

Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases

et al. 2015

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In this study we used a next generation sequencing-based approach to profile gene mutations in therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); and compared these findings with de novo MDS/AML. Consecutive bone marrow samples of 498 patients, including 70 therapy-related (28 MDS and 42 AML) and 428 de novo (147 MDS and 281 AML) were analyzed using a modified-TruSeq Amplicon Cancer Panel (Illumina) covering mutation hotspots of 53 genes. Overall, mutation(s) were detected in 58.6% of t-MDS/AML and 56.8% of de novo MDS/AML. Of therapy-related cases, mutations were detected in 71.4% of t-AML versus 39.3% t-MDS (p=0.0127). TP53 was the most common mutated gene in t-MDS (35.7%) as well as t-AML (33.3%), significantly higher than de novo MDS (17.7%) (p=0.0410) and de novo AML (12.8%) (p=0.0020). t-AML showed more frequent PTPN11 but less NPM1 and FLT3 mutations than de novo AML. In summary, t-MDS/AML shows a mutation profile different from their de novo counterparts. TP53 mutations are highly and similarly prevalent in t-MDS and t-AML but mutations in genes other than TP53 were more frequent in t-AML than t-MDS. The molecular genetic profiling further expands our understanding in this group of clinically aggressive yet heterogeneous myeloid neoplasms.

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Section: Discussionsupporting

confidence: 46%

Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases

et al. 2015

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“…4,6,8,10 The mechanisms by which PNH clones arise in immune-mediated BM failure syndromes are incompletely understood, but it is hypothesized that GPI-deficient cells have a conditional growth advantage by evading an immune attack directed against normal hematopoietic progenitor cells. Another recent hypothesis is that GPI-deficient cells, which can be detected at very low numbers in healthy individuals, can expand without a conditional advantage, especially in conditions with reduced stem cell numbers.…”

Section: Letters To the Editormentioning

confidence: 99%

“…2 Owing to a generally poor outcome of affected patients, 3 in the 2008 World Health Organization (WHO) classification, t-MDS and t-AML are not considered sufficiently distinctive and classified together under t-MN. 1 However, heterogeneous clinical outcomes have been observed, particularly within the t-MDS group, 4 and a prognostic model for t-MN would be relevant in risk-adapted therapeutic decisions. The classifications and risk-scoring systems for MDS including the French-American-British, WHO, International Prognostic Scoring System (IPSS) and WHO-based Prognostic Scoring System (WPSS) are largely based on cohorts of de novo MDS patients.…”

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confidence: 99%

Application of the International Prognostic Scoring System-Revised in therapy-related myelodysplastic syndromes and oligoblastic acute myeloid leukemia

Hasserjian

Fox

et al. 2013

Leukemia

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“…3 The prognosis of therapy-related myeloid neoplasms is poor, likely due at least in part to the high proportion of cases with adverse karyotype. 4,5 In therapy-related myelodysplastic syndrome and oligoblastic therapy-related acute myeloid leukemia, the Revised International Prognostic Scoring System has been shown to correlate with outcome, but patients with therapy-related myelodysplastic syndrome appear to do more poorly than de novo myelodysplastic syndrome within each Revised International Prognostic Scoring System riskstratum. 6,7 Unlike de novo disease, blast count is not strongly associated with outcome in therapyrelated myeloid neoplasms and therapy-related myelodysplastic syndrome and therapy-related acute myeloid leukemia are considered together as one disease entity in the 2008 World Health Organization Classification.…”

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confidence: 99%

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

Cleven

Nardi

et al. 2015

Modern Pathology

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Identification of p53-positive cells by immunohistochemistry in bone marrow from primary myelodysplastic syndrome patients correlates with the presence of TP53 mutations and poor prognosis. Mutations in the tumor suppressor gene TP53 are more frequent in therapy-related acute myeloid leukemia and myelodysplastic syndrome than in de novo disease, but the role of p53 immunohistochemistry in the therapy-related setting has not been specifically investigated. We studied p53 protein immunoreactivity in bone marrow biopsies of therapy-related myeloid neoplasms and correlated protein expression with TP53 mutation status, clinicopathologic features and outcome. We first studied 32 patients with therapy-related acute myeloid leukemia and 63 patients with therapy-related myelodysplastic syndrome/chronic myelomonocytic leukemia from one institution and then validated our results in a separate group of 32 patients with therapy-related acute myeloid leukemia and 56 patients with therapy-related myelodysplastic syndrome from a different institution. Strong p53 immunostaining in Z1% of bone marrow cells was highly predictive of a TP53 gene mutation (Po0.0001) and was strongly associated with a high-risk karyotype (Po0.0001). The presence of Z1% p53 strongly positive cells was associated with poorer overall and disease-specific survival, particularly in the subset of patients treated with stem-cell transplantation. In a multivariable Cox regression model, the presence of Z1% p53 strongly expressing cells was an independent prognostic marker for overall survival in both cohorts, with hazard ratios of 3.434 (CI: 1.751-6.735, Po0.0001) and 3.156 (CI: 1.502-6.628, P ¼ 0.002). Our data indicate that p53 protein expression, evaluated in bone marrow biopsies by a widely available immunohistochemical method, prognostically stratifies patients with therapy-related myeloid neoplasms independent of other risk factors. p53 immunostaining thus represents an easily applicable method to assess risk in therapy-related acute myeloid leukemia/myelodysplastic syndrome patients. Therapy-related myeloid neoplasms include acute myeloid leukemia, myelodysplastic syndrome, and less commonly myelodysplastic/myeloproliferative neoplasms such as chronic myelomonocytic leukemia. Therapy-related myeloid neoplasms occur as late complications of cytotoxic chemotherapy and/or radiotherapy given to treat malignancies or non-malignant conditions. 1,2 The etiology of therapy-related myeloid neoplasms is thought to be related to the mutagenic effect of cytotoxic therapy, including alkylating agents, ionizing radiation therapy, and topoisomerase inhibitors. 1 Typically, therapy-related myeloid neoplasms carry complex and usually unbalanced karyotypic abnormalities, particularly loss of material on the long arm of chromosomes 5 and 7 and rearrangements of the 11q23 region involving the MLL gene. 3 The prognosis of therapy-related myeloid neoplasms is poor, likely due at least in part to the high

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Patients with therapy-related myelodysplastic syndromes and acute myeloid leukemia share genetic features but can be separated by blast counts and cytogenetic risk profiles into prognostically relevant subgroups

Cited by 12 publications

References 8 publications

Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases

Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases

Application of the International Prognostic Scoring System-Revised in therapy-related myelodysplastic syndromes and oligoblastic acute myeloid leukemia

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

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