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

Abstract

194, no more than 200 words)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.

Mature plasmacytoid dendritic cells associated with acute myeloid leukemia show similar genetic mutations and expression profiles to leukemia cells

“…Our data, along with those from other groups, demonstrated that pDCs at different stages of maturation from AML patients exhibited the same nature of origin. Interestingly, consistent with recent studies which reported a high incidence of RUNX1 mutation 8,9 and FLT3-ITD mutaion 14 in pDC-AML patients, our two patients also carried both RUNX1 and FLT3-ITD mutations..Therefore, we speculate that FLT3-ITD mutation may also be a characteristic mutation in these patients, especially in patients with FAB M5 subtype. Moreover, neither patient was sensitive to regular chemotherapy in our study.…”

“…Tagraxofusp, an FDA-approved CD123-targeting agent has shown therapeutic potential in a patient-derived xenograft model. 9 Whether MPDMN patients will benefit from the CD123-targeting treatment remains unknown and warrants further study.…”

“…2,10 With the development of detection technology, researchers gradually realized that pDCs originated from malignant clone. [7][8][9] Two recent excellent studies 8,9 defined a subset of RUNX1 mutated AML with pDCs proliferations (pDC-AML). Neither study diagnosed pDC-AML as MPDMN due to CD34 expression on pDCs, which indicated an immature status of pDCs.…”

“…7 In AML, the genomic landscape of pDCs from AML patients was poorly studied until two recent studies defined AML patients with pDC expansion (pDC-AML) as a distinct subset of AML, characterized by a high frequency of RUNX1 mutations. 8,9 However, there is still a paucity of in-depth research on the genomic landscape and clonal origin of MPDMN in AML.…”

Reduced Plasmacytoid Dendritic Cell Output Is Associated With High Risk in Low-grade Myelodysplastic Syndrome

“…To assess ex vivo pDC differentiation and growth in MDS, we used sorted CD34+ cells to culture pDCs from 5 MDS patients, 6 umbilical cord samples, and 5 healthy donors. 16 Cord blood CD34+ cells showed 10%-20% pDCs after 2 weeks of culture and healthy donor PB CD34+ cells showed 1%-2%, whereas MDS patients showed 0%-1% pDCs (Figure 1H-J), confirming limited pDC differentiation from leukemic blasts in MDS at least in ex vivo culture.…”