Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare skin-tropic hematological malignancy of uncertain pathogenesis and poor prognosis. We examined 118 BPDCN cases for cytomorphology, MYC locus rearrangement, and MYC expression. Sixty-two (53%) and 41 (35%) cases showed the classic and immunoblastoid cytomorphology, respectively. Forty-one (38%) MYC+BPDCN (positive for rearrangement and expression) and 59 (54%) MYCBPDCN (both negative) cases were identified. Immunoblastoid cytomorphology was significantly associated with MYC+BPDCN. All examined MYC+BPDCNs were negative for MYB/MYBL1 rearrangement (0/36). Clinically, MYC+BPDCN showed older onset, poorer outcome, and localized skin tumors more commonly than MYCBPDCN. MYC was demonstrated by expression profiling as one of the clearest discriminators between CAL-1 (MYC+BPDCN) and PMDC05 (MYCBPDCN) cell lines, and its shRNA knockdown suppressed CAL-1 viability. Inhibitors for bromodomain and extra-terminal protein (BETis), and aurora kinases (AKis) inhibited CAL-1 growth more effectively than PMDC05. We further showed that a BCL2 inhibitor was effective in both CAL-1 and PMDC05, indicating that this inhibitor can be used to treat MYCBPDCN, to which BETis and AKis are probably less effective. Our data will provide a rationale for the development of new treatment strategies for patients with BPDCN, in accordance with precision medicine.

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References

  1. 1.

    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th edn. Lyon: IARC; 2017.

  2. 2.

    Leroux D. CD4+, CD56+DC2 acute leukemia is characterized by recurrent clonal chromosomal changes affecting 6 major targets: a study of 21 cases by the Groupe Francais de Cytogenetique Hematologique. Blood. 2002;99 :4154–9.

  3. 3.

    Dijkman R, van Doorn R, Szuhai K, Willemze R, Vermeer MH, Tensen CP. Gene-expression profiling and array-based CGH classify CD4 + CD56 + hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities. Blood. 2007;109:1720–7.

  4. 4.

    Lucioni M, Novara F, Fiandrino G, Riboni R, Fanoni D, Arra M, et al. Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion. Blood. 2011;118:4591–4.

  5. 5.

    Wiesner T, Obenauf AC, Cota C, Fried I, Speicher MR, Cerroni L. Alterations of the cell-cycle inhibitorsp27(KIP1) and p16(INK4a) are frequent in blastic plasmacytoid dendritic cell neoplasms. J Invest Dermatol. 2010;130:1152–7.

  6. 6.

    Jardin F, Callanan M, Penther D, Ruminy P, Troussard X, Kerckaert JP, et al. Recurrent genomic aberrations combined with deletions of various tumour suppressor genes may deregulate the G1/S transition in CD4+CD56+haematodermic neoplasms and contribute to the aggressiveness of the disease. Leukemia. 2009;23:698–707.

  7. 7.

    Laribi K, Denizon N, Besancon A, Farhi J, Lemaire P, Sandrini J, et al. Blastic plasmacytoid dendritic cell neoplasm: from origin of the cell to targeted therapies. Biol Blood Marrow Transplant. 2016;22:1357–67.

  8. 8.

    Jardin F, Ruminy P, Parmentier F, Troussard X, Vaida I, Stamatoullas A, et al. TET2 and TP53 mutations are frequently observed in blastic plasmacytoid dendritic cell neoplasm. Br J Haematol. 2011;153:413–6.

  9. 9.

    Alayed K, Patel KP, Konoplev S, Singh RR, Routbort MJ, Reddy N, et al. TET2 mutations, myelodysplastic features, and a distinct immunoprofile characterize blastic plasmacytoid dendritic cell neoplasm in the bone marrow. Am J Hematol. 2013;88:1055–61.

  10. 10.

    Menezes J, Acquadro F, Wiseman M, Gomez-Lopez G, Salgado RN, Talavera-Casanas JG, et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia. 2014;28:823–9.

  11. 11.

    Stenzinger A, Endris V, Pfarr N, Andrulis M, Johrens K, Klauschen F, et al. Targeted ultra-deep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm. Oncotarget. 2014;5:6404–13.

  12. 12.

    Sapienza MR, Fuligni F, Agostinelli C, Tripodo C, Righi S, Laginestra MA, et al. Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-kB pathway inhibition. Leukemia. 2014;28:1606–16.

  13. 13.

    Suzuki K, Suzuki Y, Hama A, Muramatsu H, Nakatochi M, Gunji M, et al. Recurrent MYB rearrangement in blastic plasmacytoid dendritic cell neoplasm. Leukemia. 2017;31:1629–1633.

  14. 14.

    Tzankov A, Hebeda K, Kremer M, Leguit R, Orazi A, van der Walt J, et al. Plasmacytoid dendritic cell proliferations and neoplasms involving the bone marrow: summary of the workshop cases submitted to the 18th Meeting of the European Association for Haematopathology (EAHP) organized by the European Bone Marrow Working Group, Basel 2016. Ann Hematol. 2017;96:765–77.

  15. 15.

    Nakamura Y, Kayano H, Kakegawa E, Miyazaki H, Nagai T, Uchida Y, et al. Identification of SUPT3H as a novel 8q24/MYC partner in blastic plasmacytoid dendritic cell neoplasm with t(6;8)(p21; q24) translocation. Blood Cancer J. 2015;5:e301.

  16. 16.

    Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110:1713–22.

  17. 17.

    Sakamoto K, Nakasone H, Togashi Y, Sakata S, Tsuyama N, Baba S, et al. ALK-positive large B-cell lymphoma: identification of EML4-ALK and a review of the literature focusing on the ALK immunohistochemical staining pattern. Int J Hematol. 2016;103:399–408.

  18. 18.

    Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, Inamura K, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res. 2009;15:3143–9.

  19. 19.

    Maeda T, Murata K, Fukushima T, Sugahara K, Tsuruda K, Anami M, et al. A novel plasmacytoid dendritic cell line, CAL-1, established from a patient with blastic natural killer cell lymphoma. Int J Hematol. 2005;81:148–54.

  20. 20.

    Narita M, Watanabe N, Yamahira A, Hashimoto S, Tochiki N, Saitoh A, et al. A leukemic plasmacytoid dendritic cell line, PMDC05, with the ability to secrete IFN-alpha by stimulation via Toll-like receptors and present antigens to naive T cells. Leuk Res. 2009;33:1224–32.

  21. 21.

    Uchibori K, Inase N, Araki M, Kamada M, Sato S, Okuno Y, et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun. 2017;8:14768.

  22. 22.

    Ogura H, Nagatake-Kobayashi Y, Adachi J, Tomonaga T, Fujita N, Katayama R. TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity. Sci Rep. 2017;7:5519.

  23. 23.

    Abraham SA, Hopcroft LE, Carrick E, Drotar ME, Dunn K, Williamson AJ, et al. Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature. 2016;534:341–6.

  24. 24.

    Mangolini M, de Boer J, Walf-Vorderwulbecke V, Pieters R, den Boer ML, Williams O. STAT3 mediates oncogenic addiction to TEL-AML1 in t(12;21) acute lymphoblastic leukemia. Blood. 2013;122:542–9.

  25. 25.

    Wiederschain D, Wee S, Chen L, Loo A, Yang G, Huang A, et al. Single-vector inducible lentiviral RNAi system for oncology target validation. Cell Cycle. 2009;8:498–504.

  26. 26.

    Trinquart L, Jacot J, Conner SC, Porcher R. Comparison of treatment effects measured by the hazard ratio and by the ratio of restricted mean survival times in oncology randomized controlled trials. J Clin Oncol. 2016;34:1813–9.

  27. 27.

    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

  28. 28.

    Momoi A, Toba K, Kawai K, Tsuchiyama J, Suzuki N, Yano T, et al. Cutaneous lymphoblastic lymphoma of putative plasmacytoid dendritic cell-precursor origin: two cases. Leuk Res. 2002;26:693–8.

  29. 29.

    Takiuchi Y, Maruoka H, Aoki K, Kato A, Ono Y, Nagano S, et al. Leukemic manifestation of blastic plasmacytoid dendritic cell neoplasm lacking skin lesion: a borderline case between acute monocytic leukemia. J Clin Exp Hematop. 2012;52:107–11.

  30. 30.

    Fu Y, Fesler M, Mahmud G, Bernreuter K, Jia D, Batanian JR. Narrowing down the common deleted region of 5q to 6.0 Mb in blastic plasmacytoid dendritic cell neoplasms. Cancer Genet. 2013;206:293–8.

  31. 31.

    Emadali A, Hoghoughi N, Duley S, Hajmirza A, Verhoeyen E, Cosset FL, et al. Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms. Blood. 2016;127:3040–53.

  32. 32.

    Ceribelli M, Hou ZE, Kelly PN, Huang DW, Wright G, Ganapathi K, et al. A druggable TCF4- and BRD4-dependent transcriptional network sustains malignancy in blastic plasmacytoid dendritic cell neoplasm. Cancer Cell. 2016;30:764–78.

  33. 33.

    Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904–17.

  34. 34.

    Amorim S, Stathis A, Gleeson M, Iyengar S, Magarotto V, Leleu X, et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016;3:e196–204.

  35. 35.

    Berthon C, Raffoux E, Thomas X, Vey N, Gomez-Roca C, Yee K, et al. Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol. 2016;3:e186–95.

  36. 36.

    Dauch D, Rudalska R, Cossa G, Nault JC, Kang TW, Wuestefeld T, et al. A MYCaurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med. 2016;22:744–53.

  37. 37.

    Yang D, Liu H, Goga A, Kim S, Yuneva M, Bishop JM. Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proc Natl Acad Sci USA. 2010;107:13836–41.

  38. 38.

    Cota C, Vale E, Viana I, Requena L, Ferrara G, Anemona L, et al. Cutaneous manifestations of blastic plasmacytoid dendritic cell neoplasm-morphologic and phenotypic variability in a series of 33 patients. Am J Surg Pathol. 2010;34:75–87.

  39. 39.

    Montero J, Stephansky J, Cai T, Griffin GK, Cabal-Hierro L, Togami K, et al. Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL2 and sensitive to venetoclax. Cancer Discov. 2017;7:156–64.

  40. 40.

    Horn H, Staiger AM, Vohringer M, Hay U, Campo E, Rosenwald A, et al. Diffuse large B-cell lymphomas of immunoblastic type are a major reservoir for MYCIGH translocations. Am J Surg Pathol. 2015;39:61–66.

  41. 41.

    van Riggelen J, Yetil A, Felsher DW. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 2010;10:301–9.

  42. 42.

    Bertrand P, Bastard C, Maingonnat C, Jardin F, Maisonneuve C, Courel MN, et al. Mapping of MYC break points in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas. Leukemia. 2007;21:515–23.

  43. 43.

    Einerson RR, Law ME, Blair HE, Kurtin PJ, McClure RF, Ketterling RP, et al. Novel FISH probes designed to detect IGK-MYC and IGL-MYC rearrangements in B-cell lineage malignancy identify a new breakpoint cluster region designated BVR2. Leukemia. 2006;20:1790–9.

  44. 44.

    Busch K, Keller T, Fuchs U, Yeh RF, Harbott J, Klose I, et al. Identification of two distinct MYC breakpoint clusters and their association with various IGH breakpoint regions in the t(8;14) translocations in sporadic Burkitt-lymphoma. Leukemia. 2007;21:1739–51.

  45. 45.

    Walker BA, Wardell CP, Brioli A, Boyle E, Kaiser MF, Begum DB, et al. Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer J. 2014;4:e191.

  46. 46.

    Bavetsias V, Linardopoulos S. Aurora kinase inhibitors: current status and outlook. Front Oncol. 2015;5:278.

  47. 47.

    Fu LL, Tian M, Li X, Li JJ, Huang J, Ouyang L, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget. 2015;6:5501–16.

  48. 48.

    Abedin SM, Boddy CS, Munshi HG. BET inhibitors in the treatment of hematologic malignancies: current insights and future prospects. Onco Targets Ther. 2016;9:5943–53.

  49. 49.

    Chaidos A, Caputo V, Karadimitris A. Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence. Ther Adv Hematol. 2015;6:128–41.

  50. 50.

    Falchook GS, Bastida CC, Kurzrock R. Aurora kinase inhibitors in oncology clinical trials: current state of the progress. Semin Oncol. 2015;42:832–48.

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Acknowledgements

This work was supported in part by grants from AMED (16cm0106203h0001 to RK and 17cm0106501h0002 to KT) and MEXT/JSPS KAKENHI (17K18338 to KS and 16H04715 to RK). The authors thank the many physicians of the cooperating institutions (listed in the online material) for providing the specimens and clinical data. The authors also thank Ms. Saki Yoshino, Ms. Sayuri Amino, Dr. Seiichi Mori, Ms. Keiko Shiozawa, Mr. Motoyoshi Iwakoshi, Ms. Tomoyo Kakita, and Ms. Yuki Togashi of the Japanese Foundation for Cancer Research for their technical support, and Ms. Sayuri Sengoku and Ms. Hiroko Nozaki for administrative assistance.

Author information

Author notes

    • Koji Izutsu

    Present address: Department of Hematology, National Cancer Center Hospital, Tokyo, Japan

Affiliations

  1. Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

    • Kana Sakamoto
    • , Reimi Asaka
    • , Seiji Sakata
    • , Satoko Baba
    • , Akito Dobashi
    •  & Kengo Takeuchi
  2. Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan

    • Kana Sakamoto
    • , Hideki Nakasone
    •  & Yoshinobu Kanda
  3. Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    • Ryohei Katayama
    •  & Sumie Koike
  4. Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

    • Reimi Asaka
    • , Naoko Tsuyama
    •  & Kengo Takeuchi
  5. Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan

    • Makoto Sasaki
  6. Department of Hematopathology, Tohoku University Graduate School of Medicine, Sendai, Japan

    • Ryo Ichinohasama
  7. Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan

    • Emi Takakuwa
  8. Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

    • Rie Yamazaki
  9. Department of Hematology, Endocrinology, and Metabolism, Faculty of Medicine, Niigata University, Niigata, Japan

    • Jun Takizawa
  10. Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    • Takahiro Maeda
  11. Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan

    • Miwako Narita
  12. Department of Hematology, Toranomon Hospital, Tokyo, Japan

    • Koji Izutsu
  13. Department of Pathology, School of Medicine, Kurume University, Kurume, Japan

    • Koichi Ohshima

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The authors declare that they have no conflict of interest.

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Correspondence to Kengo Takeuchi.

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https://doi.org/10.1038/s41375-018-0154-5

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