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MYELODYSPLASTIC NEOPLASM

Rapid growth of acquired UBA1 mutations predisposes male patients to low-risk MDS

Leukemia volume 39, pages 248–256 (2025)Cite this article

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Between June 2022 and November 2023, targeted next-generation sequencing (NGS) was performed on blood or bone marrow samples at four US medical centers. We identified 27 distinct presumably somatic UBA1 variants in 86 patients (1%, Fig. 1A). Sixty-six patients (0.7%) carried nine different pathogenic/likely pathogenic variants (PV, Fig. 1B above the protein sequence). Most were canonical loss-of-start-codon variants: p.M41T (N = 24), p.M41L (N = 21), and p.M41V (N = 14), followed by previously reported (c.118-1 G>C, N = 2) and two novel splice site variants (c.118-10_118-1 del and c.118-5_118-1 del) upstream of the p.M41 codon. Further, three VEXAS-causal missense variants p.Y55H (N = 1), p.G477A (N = 1), and p.A478S (N = 1) were also classified as PV [1, 2, 4]. An additional 18 distinct novel variants (below the protein sequence in Fig. 1B and in Supplementary Table 1), classified as variants of uncertain significance (VUS), including two recurrent variants (p.D506N and p.I890F), were identified in the remaining 20 patients (Fig. 1B, C, patients 67-86).

Thirty-one (47%) patients with UBA1 PV exhibited at least one concomitant variant, representing a significantly lower frequency compared to VUS patients (85%, p = 0.04, Fig. 1C, D and Table 1), accompanied by a lower somatic mutation burden, defined as the number of somatic variants per patient (Fig. 1E, mean ± SEM, 2.0 ± 0.2 in PV vs. 4.0 ± 0.5 in VUS, p = 0.0001). UBA1 clone sizes were notably larger in PV (Fig. 1F, mean ± SEM, 26.1% ± 1.5) than those in VUS (16.0% ± 3.3, p = 0.002). Fifty-five PV patients (83%) exhibited UBA1 variant VAFs higher than those of the leading concurrent variants, if any, indicating that UBA1 PV were the founding clones. In contrast, only 40% of VUS (Fig. 1G, p = 0.001) were the leading clones. In PV patients, DNMT3A was the most commonly mutated gene (23%), followed by TET2 (12%) and ASXL1 (6%, Fig. 1C). In VUS patients, the most prevalent concomitant variant was TET2 (Supplementary Fig. 1A, 35%, p = 0.03), followed by ASXL1 (25%, p = 0.02) and DNMT3A variants (10%, p = 0.03). Notably, variants involved in tyrosine kinase or RAS signaling pathways were significantly more prevalent in VUS patients (Supplementary Fig. 1A–C).

Table 1 The clinical diagnosis, molecular and cytogenetic profiles of 86 individuals with presumed somatic UBA1 variants.
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Fig. 1: Clonal metrics, dynamics, mutational profiles and clinical outcomes of UBA1 mutant patients with hematologic manifestation.

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Authors and Affiliations

  1. Department of Pathology, University of Utah Health, Salt Lake City, UT, USA

    Peng Li, F. N. U. Alnoor, Margaret Williams, Julie Feusier, Jay L. Patel, Anna P. Matynia, Madhu P. Menon, Rodney R. Miles, Jeffrey R. Jacobsen, Tracy I. George & Robert S. Ohgami

  2. ARUP Laboratories, Salt Lake City, UT, USA

    Peng Li, Margaret Williams, Julie Feusier, Jay L. Patel, Anna P. Matynia, Madhu P. Menon, Rodney R. Miles, Jeffrey R. Jacobsen, Tracy I. George, Philippe Szankasi, Paul Rindler, Devin Close & Robert S. Ohgami

  3. Department of Pathology & Immunology, Washington University, St. Louis, MO, USA

    F. N. U. Alnoor

  4. Department of Pathology and Laboratory Medicine, School of Medicine, Oregon Health & Science University, Portland, OR, USA

    Wei Xie & Philipp W. Raess

  5. Laboratory Medicine, Geisinger Medical Center, Danville, PA, USA

    Yi Ding

  6. Kaiser Permanente Sacramento Medical Center, Sacramento, CA, USA

    Xiangrong Zhao

  7. Mayo Clinic Laboratories, Rochester, MN, USA

    Gang Zheng

  8. Department of Pathology and Laboratory Medicine, Case Western Reserve University, Cleveland, OH, USA

    Chen Zhao

  9. Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA

    Arthur W. Zieske & Youli Zu

  10. Department of Internal Medicine, University of Utah Health, Salt Lake City, UT, USA

    Srinivas Tantravahi, Afaf Osman, Ami B. Patel, Tsewang Tashi & Douglas W. Sborov

  11. Huntsman Cancer Institute, Salt Lake City, UT, USA

    Srinivas Tantravahi, Afaf Osman, Ami B. Patel, Tsewang Tashi, Rodney R. Miles, Tracy I. George & Douglas W. Sborov

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  1. Peng Li
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Contributions

PL designed the study and drafted the manuscript. PL, FA, WX, MW, YD, GZ, CZ, AWZ, YZ, and PWR collected patients’ clinical, hematologic, pathologic, cytogenetic, and molecular data. ST, AO, ABP, TT, and DS examined patients and provided clinical information. PL, WX, MW, YD, GZ, CZ, AWZ, YZ, AM, and PR interpreted and classified all variants by NGS testing. PL, WX, MW, YD, XZ, GZ, CZ, AWZ, YZ, RRM, MM, JJ, TG, and RO examined the bone marrow biopsies. WX and PL designed the clone growth models. All authors reviewed and approved the final manuscript. CZ was supported in part by the National Institutes of Health (R01CA237006) and the U.S. Department of Veterans Affairs (I01 BX004255).

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Correspondence to Peng Li.

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Li, P., Alnoor, F.N.U., Xie, W. et al. Rapid growth of acquired UBA1 mutations predisposes male patients to low-risk MDS. Leukemia 39, 248–256 (2025). https://doi.org/10.1038/s41375-024-02397-2

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