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Acute myeloid leukemia

Mutational profiling of isolated myeloid sarcomas and utility of serum 2HG as biomarker of IDH1/2 mutations

Leukemia volume 32, pages 2008–2081 (2018)Cite this article

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Myeloid sarcoma (MS) is an extramedullary tumor mass consisting of myeloid blasts with or without maturation. MS may precede a characterized acute myeloid leukemia (AML) or can be present as an isolated tumor. Prognosis of isolated MS is typically poor despite the use of high-dose chemotherapy [1]. As isolated MS are frequently misdiagnosed for a solid tumor or lymphoma at diagnosis, molecular characterization of MS is not routinely performed, and tailored therapies based on molecular risk stratification in MS patients remained unused. Like in AML, cytogenetic abnormalities are found in around 50% of MS and mutations in NPM1 and FLT3 genes are the most frequent molecular lesions reported so far in MS [1,2,3]. A next-generation sequencing (NGS) assay including 21 genes in a series of 6 MS cases recently detected lesions in a broad spectrum of AML and myelodysplastic syndrome (MDS)-associated genes critical for epigenetic (TET2, DNMT3A, IDH2, ASXL1, EZH2), splicing (SF3B1), transcription (RUNX1, WT1), tumor suppression (TP53), or signaling (KIT, N-RAS) regulation [4].

To further characterize the mutational landscape of isolated MS, we analyzed gene mutations in cases of isolated MS using an NGS panel of 32 genes recurrently mutated in myeloid malignancies. Samples were obtained from 14 consecutive patients with histologically proven isolated de novo MS collected in 3 French centers between 2004 and 2016. Clinical and pathology data are summarized in Table 1. Conventional karyotype on MS sample was normal in the single patient with available data. Genomic DNA (gDNA) was extracted from frozen MS samples (n = 8) or formalin-fixed paraffin-embedded (FFPE) tissue samples (n = 6) and assessed for mutations in 32 genes (ASXL1, BCOR, BCORL1, CALR, CBL, CSF3R, DNMT3A, ETV6, EZH2, FLT3-TKD, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PHF6, PTPN11, RIT1, RUNX1, SETBP1, SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1, WT1, and ZRSR2). FLT3 internal tandem duplication (FLT3-ITD) mutations were investigated by fluorescent PCR and fragment analysis. NPM1, ASXL1 (including c.1934dupG; p.G646WfsX12), SRSF2, and IDH1/2 variants were confirmed by Sanger sequencing (cf Supplemental Methods). Overall, 11/14 (79%) patients presented at least 1 mutation in the selected genes. Our results are consistent with the reported high frequency of NPM1 mutation in MS (7/14) [2,3,4]. A FLT3-ITD mutation was identified in only 2 out of 10 patients in our cohort, contrasting with the higher frequency in previously reported cases [2, 4]. Mutations in IDH1 and IDH2 were predominant molecular features in our MS samples cohort (6/14 patients), including IDH2 R140Q mutation in 4/14 patients (29%), and IDH1 R132(H/C) mutation in 2/14 patients (14%). We also detected the common missense mutation SRSF2 P95(H/L) in 3/14 patients (21%). As frequently observed in AML, NPM1 mutation was associated with IDH1 R132H/C or IDH2 R140Q while SRSF2 mutation was associated with IDH2 R140Q (cf Supplemental Fig. 1). KIT mutations were found in 2/14 patients (one of which had positive type A CBFβ-MYH11 fusion transcript on MS sample) in exon 17 (D816H, D820Y) while previously reported in exon 10 [4]. Mutations were also found in NRAS in 2/14 patients (14%), PTPN11 in 2/14 patients (14%), and TP53, GATA2, RUNX1, DNMT3A mutations were each found in 1/14 patients (7%).

Table 1 Clinical and biological characteristics of 14 patients with isolated MS
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Fig. 1

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Acknowledgements

The authors thank Anne Salomon and Elisabeth Chachaty for clinical specimens, Chris Ottolenghi and Lionel Mercier for their technical assistance in 2HG analysis. This work was partly funded by the Fondation ARC pour la Recherche sur le Cancer.

Author contributions

CW, JBM, SDB, ClB, CeB, RI, and NB followed the study participants. CW collected the data and interpreted the results; AR and CQ supervised and performed molecular analysis on MS sample; SB, JD, VP, and AP performed 2HG measures; MTCM reviewed FDG-PET results; VS and JB performed the cytological and histological analyses; CW wrote the manuscript; AR, AP, VPL, and SDB supervised the project and revised the manuscript. All authors approved the manuscript.

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Author notes

  1. These authors contributed equally: Christophe Willekens, Aline Renneville.

Authors and Affiliations

  1. Département d’Hématologie, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France

    Christophe Willekens, Jean-Baptiste Micol & Stéphane De Botton

  2. Inserm U1170, Gustave Roussy, Université Paris-Saclay, 94805, Villejuif, France

    Christophe Willekens, Cyril Quivoron, Virginie Penard-Lacronique & Stéphane De Botton

  3. Centre de Biologie-Pathologie, Laboratoire d’hématologie, Centre Hospitalier Universitaire de Lille, Lille, France

    Aline Renneville & Claude Preudhomme

  4. Département de Biologie-Pathologie, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France

    Sophie Broutin, Véronique Saada, Julia Delahousse, Vianney Poinsignon, Jacques Bosq & Angelo Paci

  5. Hôpital Claude Huriez, Centre Hospitalier Universitaire Lille, Service des maladies du sang, Lille, France

    Claire Bories & Céline Berthon

  6. Département d’Hématologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, 75475, Paris, France

    Raphael Itzykson & Nicolas Boissel

  7. Département de médecine nucléaire, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France

    Marie Terroir-Cassou-Mounat

Authors
  1. Christophe Willekens
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  2. Aline Renneville
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Correspondence to Stéphane De Botton.

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SDB has conflict of interest with AGIOS and CELGENE. No potential conflicts of interest were disclosed by the other authors.

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Willekens, C., Renneville, A., Broutin, S. et al. Mutational profiling of isolated myeloid sarcomas and utility of serum 2HG as biomarker of IDH1/2 mutations. Leukemia 32, 2008–2081 (2018). https://doi.org/10.1038/s41375-018-0056-6

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