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Acquired WT1 mutations contribute to relapse of NPM1-mutated acute myeloid leukemia following allogeneic hematopoietic stem cell transplant

Bone Marrow Transplantation volume 57, pages 370–376 (2022)Cite this article

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Abstract

The role of WT1 protein in hematopoiesis and leukemogenesisis incompletely elucidated. WT1 overexpression is common in acute myeloid leukemia (AML); however, WT1 mutations occur in only about 10% of cases, with increasing incidence in the setting of relapse. In this study, we investigated the clinical and molecular characteristics of WT1 mutations in NPM1-mutated AML, to enhance our understanding of the biology and potential therapeutic implications of WT1 mutations. Our study cohort included 67 patients with NPM1 mutated AML and a median follow-up of 13.7 months. WT1 mutations were identified in 7% (n = 5) of patients at the time of initial diagnosis. WT1 mutant clones were presumed to be present as co-dominant clones in 3/5 and in subclonal populations in 2/5 cases based on variant allelic frequency (VAF) when compared with NPM1 mutation VAF. All WT1 mutations became undetectable at time of MRD-negative (NPM1-wild type) remission. None of these patients experienced relapse at the time of last follow-up (median, 15 months; range, 4.5–20.2 months). A total of 15/67 (22%) patients relapsed; among these patient, four (27%) relapsed with WT1 mutant AML. Three of four patients had undergone allogeneic hematopoietic stem cell transplantation (HSCT). None of these patients had detectable WT1 mutations at the time of initial diagnosis. WT1 mutations were presumed clonal in two cases and subclonal in the other two cases, based on VAF. Our results indicate that WT1 mutations contribute to relapse in NPM1 mutated AML, especially in the setting of HSCT. These findings suggest that emerging WT1 mutations may serve as a conduit for relapse in NPM1-mutated AML, and that sequential molecular profiling to evaluate potential emergent WT1 mutations during surveillance and particularly at relapse likely has prognostic value in patients with NPM1 mutated AML.

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Authors and Affiliations

  1. Department of Pathology, University of Rochester Medical Center, Rochester, USA

    Siba El Hussein

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

    Siba El Hussein, Joseph D. Khoury, Hong Fang, Sofia Garces, Rashmi Kanagal-Shamanna, Chi Young Ok, Keyur P. Patel, Mark J. Routbort, L. Jeffrey Medeiros, Sa A. Wang & Sanam Loghavi

  3. Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Courtney D. DiNardo, Koichi Takahashi, Ken Furudate & Farhad Ravandi

  4. Department of Oral and Maxillofacial Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan

    Ken Furudate

  5. Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

    Kirill A. Lyapichev

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  1. Siba El Hussein
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Contributions

SL and SEH: concept, study development, and manuscript original draft. CDD, KT, JDK, HF, KF, KAL, SG, RKS, CYO, KPP, MJR, FR, LJM & SAW: Critical review of manuscript, data analysis, and resources.

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Correspondence to Sanam Loghavi.

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El Hussein, S., DiNardo, C.D., Takahashi, K. et al. Acquired WT1 mutations contribute to relapse of NPM1-mutated acute myeloid leukemia following allogeneic hematopoietic stem cell transplant. Bone Marrow Transplant 57, 370–376 (2022). https://doi.org/10.1038/s41409-021-01538-w

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