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bioRxiv · 10.1101/2020.05.11.088872

Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia

Xiao, W.·Chan, A.·Waarts, M. R.·Mishra, T.·Liu, Y.·Cai, S. F.·Yao, J.·Gao, Q.·Bowman, R. L.·Koche, R.·Csete, I. S.·Baik, J.·Yanis, S.·Famulare, C.·Patel, M.·Arcila, M. E.·Stahl, M.·Rampal, R. K.·Tallman, M. S.·Zhang, Y.·Dogan, A.·Goldberg, A. D.·Roshal, M.·Levine, R.
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Abstract

Plasmacytoid dendritic cells (pDC) are the principal natural type I interferon producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia (CMML). The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here we characterize AML patients with pDC expansion (pDC-AML), which we observe in approximately 5% of AML. pDC-AML often possess crosslineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without PDC expansion. We demonstrate that pDCs are clonally related to, and originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells towards pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.Competing Interest StatementConflict-of-interest disclosure: W.X. has received research support from Stemline Therapeutics. S.F.C. is a consultant for Imago Biosciences and has received honoraria from DAVA Oncology. A.D.G. served on advisory boards or as a consultant for Abbvie, Aptose, Celgene, Daiichi Sanyko, Genentech, received research funding from Abbvie, ADC Therapeutics, Aprea, AROG, Daiichi Sanyko, Pfizer, received Honoraria from Dava Oncology. R.K.R has received consulting fees from: Constellation, Incyte, Celgene, Promedior, CTI, Jazz Pharmaceuticals, Blueprint, Stemline, and research funding from Incyte, Constellation, and Stemline Therapeutics. M.S.T has received research funding from AbbVie, Cellerant, Orsenix, ADC Therapeutics, Biosight, Glycomimetics, Rafael Pharmaceuticals and Amgen. He also served on advisory Boards for AbbVie, BioLineRx, Daiichi-Sankyo, Orsenix, KAHR, Rigel, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze, Jazz Pharma, Roche, Biosight and Novartis. He received royalties from UpToDate. R.L.L. is on the supervisory board of Qiagen and is a scientific advisor to Loxo (until 2019), Auron, Ajax, Mission Bio, Imago, C4 Therapeutics and Isoplexis, which each include an equity interest. He receives research support from and consulted for Celgene and Roche, he has received research support from Prelude Therapeutics, and he has consulted for Incyte, Novartis and Janssen. He has received honoraria from Lilly and Amgen for invited lectures and from Gilead for grant reviews.View Full Text

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Xiao, W., Chan, A., Waarts, M. R., Mishra, T., Liu, Y., Cai, S. F., Yao, J., Gao, Q., Bowman, R. L., Koche, R., Csete, I. S., Baik, J., Yanis, S., Famulare, C., Patel, M., Arcila, M. E., Stahl, M., Rampal, R. K., Tallman, M. S., Zhang, Y., Dogan, A., Goldberg, A. D., Roshal, M., Levine, R.. 2020-05-13. Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia. https://doi.org/10.1101/2020.05.11.088872

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