Skip to main content
SpringerLink
Log in

Emergence of clone with PHF6 nonsense mutation in chronic myelomonocytic leukemia at relapse after allogeneic HCT

  • Case Report
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Disease relapse is a major cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) and the mechanisms of relapse remain unclear. We encountered a 58-year-old man with chronic myelomonocytic leukemia (CMML) that relapsed after haploidentical HCT from his daughter. Peripheral blood samples collected at HCT and at relapse were analyzed, and CD14+/CD16− monocytes that typically accumulate in CMML were isolated by flow cytometry. Whole-exome sequencing of the monocytes revealed 8 common mutations in CMML at HCT. In addition, a PHF6 nonsense mutation not detected at HCT was detected at relapse. RNA sequencing could not detect changes in expression of HLA or immune-checkpoint molecules, which are important mechanisms of immune evasion. However, gene set enrichment analysis (GSEA) revealed that a TNF-α signaling pathway was downregulated at relapse. Ubiquitination of histone H2B at lysine residue 120 (H2BK120ub) at relapse was significantly decreased at the protein level, indicating that PHF6 loss might downregulate a TNF-α signaling pathway by reduction of H2BK120ub. This case illustrates that PHF6 loss contributes to a competitive advantage for the clone under stress conditions and leads to relapse after HCT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Zeiser R, Vago L. Mechanisms of immune escape after allogeneic hematopoietic cell transplantation. Blood. 2019;133:1290–7.

    Article  CAS  Google Scholar 

  2. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  CAS  Google Scholar 

  3. Valent P, Orazi A, Savona MR, Patnaik MM, Onida F, van de Loosdrecht AA, et al. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions. Haematologica. 2019;104:1935–49.

    Article  CAS  Google Scholar 

  4. Savona MR, Malcovati L, Komrokji R, Tiu RV, Mughal TI, Orazi A, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015;125:1857–65.

    Article  CAS  Google Scholar 

  5. Selimoglu-Buet D, Wagner-Ballon O, Saada V, Bardet V, Itzykson R, Bencheikh L, et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia. Blood. 2015;125:3618–26.

    Article  CAS  Google Scholar 

  6. Patnaik MM, Tefferi A. Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia. Blood Cancer J. 2016;6: e393.

    Article  CAS  Google Scholar 

  7. Patel BJ, Przychodzen B, Thota S, Radivoyevitch T, Visconte V, Kuzmanovic T, et al. Genomic determinants of chronic myelomonocytic leukemia. Leukemia. 2017;31:2815–23.

    Article  CAS  Google Scholar 

  8. Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31:2428–36.

    Article  CAS  Google Scholar 

  9. Gagelmann N, Badbaran A, Beelen DW, Salit RB, Stolzel F, Rautenberg C, et al. A prognostic score including mutation profile and clinical features for patients with CMML undergoing stem cell transplantation. Blood Adv. 2021;5:1760–9.

    Article  CAS  Google Scholar 

  10. Christopher MJ, Petti AA, Rettig MP, Miller CA, Chendamarai E, Duncavage EJ, et al. Immune escape of relapsed AML cells after allogeneic transplantation. N Engl J Med. 2018;379:2330–41.

    Article  CAS  Google Scholar 

  11. Toffalori C, Zito L, Gambacorta V, Riba M, Oliveira G, Bucci G, et al. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation. Nat Med. 2019;25:603–11.

    Article  CAS  Google Scholar 

  12. Miyagi S, Sroczynska P, Kato Y, Nakajima-Takagi Y, Oshima M, Rizq O, et al. The chromatin-binding protein Phf6 restricts the self-renewal of hematopoietic stem cells. Blood. 2019;133:2495–506.

    Article  CAS  Google Scholar 

  13. Pronk CJ, Veiby OP, Bryder D, Jacobsen SE. Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors. J Exp Med. 2011;208:1563–70.

    Article  CAS  Google Scholar 

  14. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  Google Scholar 

  15. Mullican SE, Zhang S, Konopleva M, Ruvolo V, Andreeff M, Milbrandt J, et al. Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat Med. 2007;13:730–5.

    Article  CAS  Google Scholar 

  16. Ramirez-Herrick AM, Mullican SE, Sheehan AM, Conneely OM. Reduced NR4A gene dosage leads to mixed myelodysplastic/myeloproliferative neoplasms in mice. Blood. 2011;117:2681–90.

    Article  CAS  Google Scholar 

  17. Song MA, Tiirikainen M, Kwee S, Okimoto G, Yu H, Wong LL. Elucidating the landscape of aberrant DNA methylation in hepatocellular carcinoma. PLoS One. 2013;8: e55761.

    Article  CAS  Google Scholar 

  18. Palomo L, Malinverni R, Cabezon M, Xicoy B, Arnan M, Coll R, et al. DNA methylation profile in chronic myelomonocytic leukemia associates with distinct clinical, biological and genetic features. Epigenetics. 2018;13:8–18.

    Article  Google Scholar 

  19. Meacham CE, Lawton LN, Soto-Feliciano YM, Pritchard JR, Joughin BA, Ehrenberger T, et al. A genome-scale in vivo loss-of-function screen identifies Phf6 as a lineage-specific regulator of leukemia cell growth. Genes Dev. 2015;29:483–8.

    Article  CAS  Google Scholar 

  20. Oh S, Boo K, Kim J, Baek SA, Jeon Y, You J, et al. The chromatin-binding protein PHF6 functions as an E3 ubiquitin ligase of H2BK120 via H2BK12Ac recognition for activation of trophectodermal genes. Nucleic Acids Res. 2020;48:9037–52.

    Article  CAS  Google Scholar 

  21. Cao J, Yan Q. Histone ubiquitination and deubiquitination in transcription, DNA damage response, and cancer. Front Oncol. 2012;2:26.

    Article  Google Scholar 

  22. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550–61.

    Article  CAS  Google Scholar 

  23. Franzini A, Pomicter AD, Yan D, Khorashad JS, Tantravahi SK, Than H, et al. The transcriptome of CMML monocytes is highly inflammatory and reflects leukemia-specific and age-related alterations. Blood Adv. 2019;3:2949–61.

    Article  CAS  Google Scholar 

  24. Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat CV, Balbin M, et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia. 2011;25:130–4.

    Article  Google Scholar 

  25. Quek L, Ferguson P, Metzner M, Ahmed I, Kennedy A, Garnett C, et al. Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia. Blood Adv. 2016;1:193–204.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank all the clinicians at our center who helped obtain data for this study. Y. Akahoshi is a Research Fellow of Japan Society of the Promotion of Science (JSPS).

Author information

Authors and Affiliations

  1. Division of Hematology, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama, Saitama, 330-8503, Japan

    Yu Akahoshi, Hideki Nakasone, Machiko Kusuda, Kazuaki Kameda, Yuhei Nakamura, Masakatsu Kawamura, Junko Takeshita, Shunto Kawamura, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Shimpei Matsumi, Ayumi Gomyo, Aki Tanihara, Masaharu Tamaki, Shun-ichi Kimura, Shinichi Kako & Yoshinobu Kanda

Authors
  1. Yu Akahoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideki Nakasone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Machiko Kusuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuaki Kameda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuhei Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masakatsu Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Junko Takeshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shunto Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nozomu Yoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yukiko Misaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kazuki Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shimpei Matsumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ayumi Gomyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Aki Tanihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Masaharu Tamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Shun-ichi Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Shinichi Kako
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yoshinobu Kanda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YA designed the study, performed the experiments, collected data, analyzed data, and wrote the manuscript. HN advised on methods and reviewed the manuscript. MKu, KK, YN, MKa, JT, SKa, NY, YM, KY, SM, AG, AT, MT, S-iK, and SKa collected important data. YK reviewed the manuscript, revised the manuscript, and organized this project.

Corresponding author

Correspondence to Yoshinobu Kanda.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest for this study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 19 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akahoshi, Y., Nakasone, H., Kusuda, M. et al. Emergence of clone with PHF6 nonsense mutation in chronic myelomonocytic leukemia at relapse after allogeneic HCT. Int J Hematol 115, 748–752 (2022). https://doi.org/10.1007/s12185-021-03284-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-021-03284-7

Keywords

Search

Navigation