Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia

Rothenberg‐Thurley, Maja; Amler, S; Goerlich, D; Köhnke, Thomas; Konstandin, Nikola P.; Schneider, Simon; Sauerland, M C; Herold, Tobias; Hubmann, Max; Ksienzyk, Bianka; Zellmeier, Evelyn; Bohlander, Stefan K.; Subklewe, Marion; Faldum, A; Hiddemann, Wolfgang; Braess, Jan; Spiekermann, Karsten; Metzeler, Klaus H.

doi:10.1038/leu.2017.350

Cited by 24 publications

(25 citation statements)

References 29 publications

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“…In fact, age-related clonal hematopoiesis (ARCH) is driven by mutations also commonly found in MDS and AML (e.g. especially in the genes DNMT3A, TET2, ASXL1, JAK2 , or TP53 ) [ 11 , 12 , 21 , 22 , 23 ]. The condition is associated with an increased risk to develop a myeloid malignancy including MDS, as well as with an increased all-cause mortality, especially by cardio-vascular events [ 11 , 12 ].…”

Section: The Molecular Landscape In Mdsmentioning

confidence: 99%

Myelodysplastic syndromes: Biological and therapeutic consequences of the evolving molecular aberrations landscape

et al. 2021

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Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with heterogeneous presentation, ranging from indolent disease courses to aggressive diseases similar to acute myeloid leukemia (AML). Approximately 90% of MDS patients harbor recurrent mutations , which – with the exception of mutated SF3B1 –have not (yet) been included into the diagnostic criteria or risk stratification for MDS. Accumulating evidence suggests their utility for diagnostic workup, treatment indication and prognosis. Subsequently, in patients with unexplained cytopenia or dysplasia identification of these mutations may lead to earlier diagnosis. The acquisition and expansion of additional driver mutations usually antecedes further disease progression to higher risk MDS or secondary AML and thus, can be clinically helpful to detect individuals that may benefit from aggressive treatment approaches. Here, we review our current understanding of somatic gene mutations, gene expression patterns and flow cytometry regarding their relevance for disease evolution from pre-neoplastic states to MDS and potentially AML.

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Section: The Molecular Landscape In Mdsmentioning

confidence: 99%

Myelodysplastic syndromes: Biological and therapeutic consequences of the evolving molecular aberrations landscape

et al. 2021

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“…Moreover, AML relapse was characterized by the expansion of the FLT3 -ITD clone that was reduced but not eradicated by the treatment, with an increase of allelic ratio from 0.09 (diagnosis) to 0.21 (relapse). A recent study showed that the persistence of DNMT3A mutation at a VAF ≥2% at first remission is a common event in AML, occurring in 65% of cases with mutation at diagnosis and is associated with older age and inferior relapse-free survival [32].…”

Section: Resultsmentioning

confidence: 99%

Identification of Two DNMT3A Mutations Compromising Protein Stability and Methylation Capacity in Acute Myeloid Leukemia

Bruno

Bochicchio

Franchini

et al. 2019

Journal of Oncology

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Somatic mutations of DNMT3A occur in about 20% of acute myeloid leukemia (AML) patients. They mostly consist in heterozygous missense mutations targeting a hotspot site at R882 codon, which exhibit a dominant negative effect and are associated with high myeloblast count, advanced age, and poor prognosis. Other types of mutations such as truncations, insertions, or single-nucleotide deletion also affect the DNMT3A gene, though with lower frequency. The present study aimed to characterize two DNMT3A gene mutations identified by next-generation sequencing (NGS), through analysis of protein stability and DNA methylation status at CpG islands. The first mutation was a single-nucleotide variant of DNMT3A at exon 20 causing a premature STOP codon (c.2385G > A; p.Trp795∗; NM_022552.4). The DNMT3A mutation load increased from 4.5% to 38.2% during guadecitabine treatment, with a dominant negative effect on CpG methylation and on protein expression. The second mutation was a novel insertion of 35 nucleotides in exon 22 of DNMT3A (NM_022552.4) that introduced a STOP codon too, after the amino acid Glu863 caused by a frameshift insertion (c.2586_2587insTCATGAATGAGAAAGAGGACATCTTATGGTGCACT; p. Thr862_Glu863fsins). The mutation, which was associated with reduced DNMT3A expression and CpG methylation, persisted at relapse with minor changes in the methylation profile and at protein level. Our data highlight the need to better understand the consequences of DNMT3A mutations other than R882 substitutions in the leukemogenic process in order to tailor patient treatments, thus avoiding therapeutic resistance and disease relapse.

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“…Despite the observed negative selection against cells with biallelic TET2 mutation in vivo, 5-Aza treatment rarely resulted in the complete elimination of TET2 null cells, consistent with data from the index patient in whom 5'-Aza-induced morphological remission was characterized by the persistence of cells with biallelic TET2 mutation. Mutation persistence in morphological remission has been reported for several leukemia driver genes, including those characteristic of age-associated clonal hematopoiesis such as TET2, DNMT3A, SRSF2, RUNX1 and ASXL1 [32][33][34][35] .…”

Section: Discussionmentioning

confidence: 99%

Biallelic TET2 mutation sensitizes to 5’-azacitidine in acute myeloid leukemia

Stölzel

Fordham

Lin

et al. 2021

Preprint

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Precision medicine can significantly improve outcomes for cancer patients, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here we describe somatic biallelic TET2 mutation (focal deletion and nonsense mutation) in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine, but acutely sensitive to 5-azacitidine (5-Aza) hypomethylating monotherapy, resulting in long-term morphological remission (overall survival (OS) 850 days). Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5-Aza compared to cells with monoallelic mutation. We subsequently identified 29 additional patients from the Study Alliance Leukemia biobank with chromosome 4 abnormalities and identified two further patients with complex biallelic TET2 mutations, including one with trisomy 4, homozygosity across the long arm and an inactivating point mutation. We also screened patients recruited to the PETHEMA FLUGAZA phase 3 clinical trial and identified three patients with biallelic TET2 mutations, two of whom had responded very well to single agent 5-Aza (OS 767 and 579 days) despite having adverse risk AML and poor performance status. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for cancer patients.

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Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia

Cited by 24 publications

References 29 publications

Myelodysplastic syndromes: Biological and therapeutic consequences of the evolving molecular aberrations landscape

Myelodysplastic syndromes: Biological and therapeutic consequences of the evolving molecular aberrations landscape

Identification of Two DNMT3A Mutations Compromising Protein Stability and Methylation Capacity in Acute Myeloid Leukemia

Biallelic TET2 mutation sensitizes to 5’-azacitidine in acute myeloid leukemia

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