Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

Kühnl, Andrea; Valk, Peter J.M.; Sanders, Mathijs A.; Ivey, Adam; Hills, Robert Kerrin; Mills, Ken I.; Gale, Rosemary E.; Kaiser, Martin; Dillon, Richard; Joannides, Melanie; Gilkes, Amanda F.; Haferlach, Torsten; Schnittger, Susanne; Duprez, Estelle; Linch, David C.; Delwel, Ruud; Löwenberg, Bob; Baldus, Claudia D.; Solomon, Ellen; Burnett, Alan Kenneth; Grimwade, David

doi:10.1182/blood-2014-12-613703

Cited by 45 publications

(47 citation statements)

References 50 publications

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“…This is highlighted by the commonest subtype of AML, defined by the NPM1c mutation, which exhibits considerable molecular complexity ( Figure 5). 9, 100 We already know that the addition of DNMT3A or FLT3-ITD mutations alter the prognostic significance of NPM1c mutations in patients treated with standard "7 1 3"-like AML therapy. However the prognostic significance of additional mutations or combinations of mutations is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

Grimwade

Ivey

Huntly

2016

Blood

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363

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Recent major advances in understanding the molecular basis of acute myeloid leukemia (AML) provide a double-edged sword. Although defining the topology and key features of the molecular landscape are fundamental to development of novel treatment approaches and provide opportunities for greater individualization of therapy, confirmation of the genetic complexity presents a huge challenge to successful translation into routine clinical practice. It is now clear that many genes are recurrently mutated in AML; moreover, individual leukemias harbor multiple mutations and are potentially composed of subclones with differing mutational composition, rendering each patient’s AML genetically unique. In order to make sense of the overwhelming mutational data and capitalize on this clinically, it is important to identify (1) critical AML-defining molecular abnormalities that distinguish biological disease entities; (2) mutations, typically arising in subclones, that may influence prognosis but are unlikely to be ideal therapeutic targets; (3) mutations associated with preleukemic clones; and (4) mutations that have been robustly shown to confer independent prognostic information or are therapeutically relevant. The reward of identifying AML-defining molecular lesions present in all leukemic populations (including subclones) has been exemplified by acute promyelocytic leukemia, where successful targeting of the underlying PML-RARα oncoprotein has eliminated the need for chemotherapy for disease cure. Despite the molecular heterogeneity and recognizing that treatment options for other forms of AML are limited, this review will consider the scope for using novel molecular information to improve diagnosis, identify subsets of patients eligible for targeted therapies, refine outcome prediction, and track treatment response.

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Section: Discussionmentioning

confidence: 99%

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

Grimwade

Ivey

Huntly

2016

Blood

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363

300

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“…Additional details are provided in Table S1 in Supplementary Appendix 1. GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG TCTG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG CATG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG CCTG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG CTTG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG TATG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG TCGG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG CAGG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG TAAG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG CGTG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG TTTG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG CAAA GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG TAGG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG CTCG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG CAGA GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG CCGG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG TCAG GCTATTCAAGATCTCTG GCAGTGGAGGAAGTCTCTTTAAGAAAATAG TTCG GCTATTCAAGATCTCTG CAGTGGAGGAAGTCTCTTTAAGAAAATAG CCGTT GCTATTCAAGATCTCTG AAGTCTCTTTAAGAAAATAG TCAAGACTTTCTTA GCTATTCAAGATCTCTG TCTCTTTAAGAAAATAG TCGGAGTCTCGGCGGAC GCTATTCAAGATCTC TGGCAGTGGAGGAAGTCTCTTTAAGAAAATAG ACAA GCTATTCAAGATCTC TGGAGGAAGTCTCTTTAAGAAAATAG TCCATGCTCC GCTATTCAAGATCTCTGGCAG TGGAGGAAGTCTCTTTAAGAAAATAG CGGA GCTATTCAAGATCTCTGGCAG TGGAGGAAGTCTCTTTAAGAAAATAG AGGC GCTATTCAAGATCTCTGGCAGT GTCTCTTTAAGAAAATAG CTTTCGCTCAC GCTATTCAAGATCTCTGGCAGTG AAGTCTCTTTAAGAAAATAG TTTTGCTC GCTATTCAAGATCTCTGGCAGTG 31 Diagnostic DNA from 223 samples obtained from patients with NPM1-mutated AML was sequenced, and additional mutations (median number, 3; range, 1 to 8) were identified in 222 samples (99.6%), with a median read depth of 1280× (range, 51 to 6700). We determined the freq...…”

Section: Amplification Of Npm1-mutated Transcriptsmentioning

confidence: 99%

“…31 The genes represented on this panel were selected on the basis of the Cancer Genome Atlas (TCGA) data 2 and on data obtained by exome-sequencing analysis of 19 diagnostic samples and 11 relapse samples obtained from 22 study cohort patients; of these patients, 5 were in ongoing complete remission and 17 were subject to relapse. On the basis of the exome-sequencing data, included in the panel were CCND3, CTCF, KDM3B, KDM6A, KMT2D, LZTR1, MYC, NIPBL, POT1, SS18, and ZBTB7A.…”

mentioning

confidence: 99%

Assessment of Minimal Residual Disease in Standard-Risk AML

Ivey

Hills

Simpson³

et al. 2016

N Engl J Med

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BACKGROUNDDespite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. METHODSWe used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. RESULTSMolecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status. CONCLUSIONSThe presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors.

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“…6 However, our understanding of Wnt signaling in hematopoietic cells is incomplete; a holistic view is needed to understand how alterations to Wnt pathway components affect disease processes. This was most recently illustrated in a paper in Blood by Kühnl et al,7 who examined the role of the putative tumor suppressor CXXC5, a CXXC-type Zn-finger protein that interacts with disheveled (DVL) and impairs Wnt signaling in leukemia cell lines. Contrary to expectations, in AMLs, downregulation of CXXC5 expression via epigenetic silencing was associated with upregulation of cell cycling genes, coordinated with downregulation of genes implicated in leukemogenesis (eg, WT1, GATA2, KMT2A/MLL, DNMT3B, and RUNX1), and a better prognosis.…”

mentioning

confidence: 99%

Haploinsufficient loss of multiple 5q genes may fine-tune Wnt signaling in del(5q) therapy-related myeloid neoplasms

Stoddart

Nakitandwe

Chen

et al. 2015

Blood

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Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

Cited by 45 publications

References 50 publications

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

Assessment of Minimal Residual Disease in Standard-Risk AML

Haploinsufficient loss of multiple 5q genes may fine-tune Wnt signaling in del(5q) therapy-related myeloid neoplasms

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