The Origin and Evolution of Mutations in Acute Myeloid Leukemia

Welch, John S.; Ley, Timothy J.; Link, Daniel C.; Miller, Christopher A.; Larson, David E.; Koboldt, Daniel C.; Wartman, Lukas D.; Lamprecht, Tamara; Liu, Fulu; Xia, Jun; Kandoth, Cyriac; Fulton, Robert S.; McLellan, Michael D.; Dooling, David J.; Wallis, John W.; Chen, Ken; Harris, Christopher; Schmidt, Heather; Kalicki-Veizer, Joelle; Lu, Charles; Zhang, Qunyuan; Li, Gang; O’Laughlin, Michelle; McMichael, Joshua F.; Delehaunty, Kim D.; Fulton, Lucinda A.; Magrini, Vincent; McGrath, Sean; Demeter, Ryan; Vickery, Tammi L.; Hundal, Jasreet; Cook, Lisa L.; Swift, Gary W.; Reed, Jerry P.; Alldredge, Patricia A.; Wylie, Todd; Walker, Jason; Watson, Mark A.; Heath, Sharon E.; Shannon, William D.; Varghese, Nobish; Nagarajan, Rakesh; Payton, Jacqueline E.; Baty, Jack; Kulkarni, Shashikant; Klco, Jeffery M.; Tomasson, Michael H.; Westervelt, Peter; Walter, Matthew J.; Graubert, Timothy A.; DiPersio, John F.; Li, Ding; Mardis, Elaine R.; Wilson, Richard K.

doi:10.1016/j.cell.2012.06.023

Cited by 1,401 publications

(1,296 citation statements)

References 80 publications

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“…The proposition that these clock-like mutations derive from normal cells is supported by the observation that the profile of signatures 1 and 5 combined is very similar to the somatic mutational patterns observed in the small set of non-neoplastic human somatic cells thus far sequenced 11 . Moreover, a combination of signatures 1 and 5 also recapitulates the pattern of de novo mutations found in the human germline (data from refs.…”

Section: Discussionmentioning

confidence: 79%

Clock-like mutational processes in human somatic cells

et al. 2015

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During the course of a lifetime somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This study provides the first survey of clock-like mutational processes operative in human somatic cells.

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Section: Discussionmentioning

confidence: 79%

Clock-like mutational processes in human somatic cells

et al. 2015

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“…No individuals with somatic variants at these loci were identified. Whilst our findings could be explained by a rarity of driver mutations, the fact that human HSCs accrue somatic variants from the first decade of life (Welch et al , 2012) proposes the alternative possibility that such mutations may not confer clonal advantage in the young.…”

mentioning

confidence: 80%

“…In light of the above, our findings have two plausible explanations: (i) that somatic driver mutations are very uncommon in young individuals even after exposure to chemotherapy or (ii) that accrual of such mutations is insufficient to trigger clonal expansion in this age group. The latter is supported by findings that oncogenic mutations begin accumulating early in life (Welch et al , 2012) and that cancer‐associated mutations are less able to drive clonal expansion in young compared to old stem cells (Zhu et al , 2016). The fact that bona‐fide driver mutations do not always lead to haematopoietic clonal expansion, even after several years, was highlighted by Young et al (2016), using ultra‐sensitive sequencing.…”

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confidence: 88%

Clonal haematopoiesis is not prevalent in survivors of childhood cancer

et al. 2017

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“…We also determined that the biologic effects of SP2509 treatment were also phenocopied by shRNA mediated knockdown of LSD1 in AML cells, suggesting that the effects of SP2509 were mediated by LSD1 inhibition. Recent reports have highlighted that the NPM1 mutation is the founder mutation in the AML stem/progenitor cells where acquisition of FLT3-ITD mutation results in the emergence of an aggressive AML phenotype (4,34). In our studies, SP2509 exerted a relatively higher level of activity against AML cells expressing NPM1 mutation.…”

Section: Sp2509 Is a Small Molecule Reversible Inhibitor Of Lsd1 (19)mentioning

confidence: 48%

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

Fiskus¹,

Sharma²,

Shah³

et al. 2017

Leukemia

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The histone demethylase LSD1 (KDM1A) demethylates mono-and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in AML. Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the co-repressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and C/EBPα in cultured AML cells. Additionally, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphologic features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than MLL fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Cotreatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared to each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML. KeywordsKDM1A; histone deacetylase inhibitor; acute myeloid leukemia; differentiation Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use

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The Origin and Evolution of Mutations in Acute Myeloid Leukemia

Cited by 1,401 publications

References 80 publications

Clock-like mutational processes in human somatic cells

Clock-like mutational processes in human somatic cells

Clonal haematopoiesis is not prevalent in survivors of childhood cancer

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

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