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Acute myeloid leukemia

The Clinical impact of PTPN11 mutations in adults with acute myeloid leukemia

Leukemia volume 35, pages 691–700 (2021)Cite this article

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Abstract

While germline and somatic mutations in the gene PTPN11, encoding a phosphatase which regulates the RAS signaling pathway, are well characterized in children with Noonan syndrome and juvenile myelomonocytic leukemia, less is known about their clinical impact in adults with acute myeloid leukemia (AML). To elucidate the effect of PTPN11 mutations (PTPN11mut) on clinical outcomes, we screened adult patients with AML treated at our institution using targeted next-generation sequencing. Among 1406 consecutive patients, 112 (8%) had PTPN11mut. These mutations were more commonly associated with the acute myelomonocytic/monocytic leukemia subtype than was wild-type PTPN11, while none were detected in patients with core-binding factor AML. They co-occurred more commonly with NPM1 mutations and FLT3 internal tandem duplications and less commonly with mutations in IDH2 and a complex karyotype. Compared with the wild-type allele, PTPN11mut was associated with lower complete response rates (54% vs 40%; P = 0.04), and shorter overall survival (median 13.6 vs 8.4 months; P = 0.008). In a multivariate analysis, PTPN11mut independently increased the risk of death, with a hazard ratio of 1.69 (95% CI, 1.25–2.29; P = 0.0007). In summary, mutations in PTPN11 have a characteristic phenotype in adults with AML and are associated with an adverse prognosis.

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Fig. 1: Landscape of PTPN11 mutations in adult AML.
Fig. 2: Influence of mutations in PTPN11 on survival.
Fig. 3: Impact of PTPN11 mutational status and ELN risk stratification on overall survival.

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Acknowledgements

This work was supported in part by the National Institutes of Health/National Cancer Institute through MD Anderson’s Cancer Center Support Grant P30 CA016672 and the MD Anderson Cancer Center Leukemia SPORE P50 CA100632; by the Charif Souki Cancer Research Fund; and by generous philanthropic contributions to the MD Anderson Moon Shots Program. GCI has received funding through the National Cancer Institute K12 Paul Calabresi Clinical Scholarship Award (NIH/NCI K12 CA088084). Editorial support was provided by Amy Ninetto in Scientific Publications, Research Medical Library, The University of Texas MD Anderson Cancer Center.

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  1. These authors contributed equally: Mansour Alfayez, Ghayas C. Issa

Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Mansour Alfayez, Ghayas C. Issa, Nicholas J. Short, Jorge E. Cortes, Tapan Kadia, Farhad Ravandi, Sherry Pierce, Rita Assi, Guillermo Garcia-Manero, Courtney D. DiNardo, Naval Daver, Naveen Pemmaraju, Hagop Kantarjian & Gautam Borthakur

  2. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Keyur P. Patel

  3. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Feng Wang

  4. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Xuemei Wang

  5. Lebanese American University and Lebanese American University Medical Center-Rizk Hospital, Beirut, Lebanon

    Rita Assi

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Contributions

MA, GCI, GB, and HK analyzed the data and wrote the article. MA, GCI, SP, and FW compiled and summarized the data. XW provided statistical support and analysis. MA, GCI, and FG analyzed the genomic data. KP performed next-generation sequencing and analysis. JC, FR, TK, ND, GGM, CD, NP, HK, and GB enrolled patients.

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Correspondence to Gautam Borthakur.

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Alfayez, M., Issa, G.C., Patel, K.P. et al. The Clinical impact of PTPN11 mutations in adults with acute myeloid leukemia. Leukemia 35, 691–700 (2021). https://doi.org/10.1038/s41375-020-0920-z

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