Plasmacytoid dendritic cells proliferation associated with acute myeloid leukemia: phenotype profile and mutation landscape

Abstract

Neoplasms involving plasmacytoid Dendritic Cells (pDCs) include Blastic pDC Neoplasms (BPDCN) and other pDC proliferations, where pDCs are associated with myeloid malignancies: most frequently Chronic MyeloMonocytic Leukemia (CMML) but also Acute Myeloid Leukemia (AML), hereafter named pDC-AML. We aimed to determine the reactive or neoplastic origin of pDCs in pDC-AML, and their link with the CD34+ blasts, monocytes or conventional DCs (cDCs) associated in the same sample, by phenotypic and molecular analyses (targeted NGS, 70 genes). We compared 15 pDC-AML at diagnosis with 21 BPDCN and 11 normal pDCs from healthy donors. CD45low CD34+ blasts were found in all cases (10-80% of medullar cells), associated with pDCs (4-36%), monocytes in 14 cases (1-10%) and cDCs (2 cases, 4.8-19%). pDCs in pDC-AML harbor a clearly different phenotype from BPDCN: CD4+ CD56- in 100% of cases, most frequently CD303+, CD304+ and CD34+; lower expression of cTCL1 and CD123 with isolated lymphoid markers (CD22/CD7/CD5) in some cases, suggesting a pre-pDC stage. In all cases, pDCs, monocytes and cDC are neoplastic since they harbor the same mutations as CD34+ blasts. RUNX1 is the most commonly mutated gene: detected in all AML with minimal differentiation (M0-AML) but not in the other cases. Despite low number of cases, the systematic association between M0-AML, RUNX1 mutations and an excess of pDC is puzzling. Further evaluation in a larger cohort is required to confirm RUNX1 mutations in pDC-AML with minimal differentiation and to investigate whether it represents a proliferation of blasts with macrophage and DC progenitor potential.

The Plasmacytoid Dendritic Cell CD123+ Compartment in Acute Leukemia with or without RUNX1 Mutation: High Inter-Patient Variability Disclosed by Immunophenotypic Unsupervised Analysis and Clustering

“…The stable pattern in normal BM gives even more weight to the astonishing diversity disclosed in the seven cases analyzed here. Indeed, it could have been expected that the RUNX1 mut signature would be associated with PDC differentiation [6,7] but several intriguing facts may be noted.…”

“…RUNX1 mut AML is most often purely blastic by cytological assessment and myeloperoxidase-negative, corresponding to AML with minimal differentiation [2][3][4]. In some leukemias with RUNX1 mut , mixed-phenotype acute leukemia (MPAL) characteristics can, however, be present [5], and RUNX1 mut has also been associated with AML cases with a plasmacytoid dendritic cell (PDC) component [6,7]. However, RUNX1 mut has only seldom been reported in blastic PDC neoplasms (BPDCN) [6,8], while clusters of mature PDCs have been described in bone marrow (BM) biopsies from patients with MPN or MDS/MPN [9].…”

“…In some leukemias with RUNX1 mut , mixed-phenotype acute leukemia (MPAL) characteristics can, however, be present [5], and RUNX1 mut has also been associated with AML cases with a plasmacytoid dendritic cell (PDC) component [6,7]. However, RUNX1 mut has only seldom been reported in blastic PDC neoplasms (BPDCN) [6,8], while clusters of mature PDCs have been described in bone marrow (BM) biopsies from patients with MPN or MDS/MPN [9]. An association of BPDCN with CMML has also been reported [10,11].…”

The Role of Plasmacytoid Dendritic Cells in Cancers

“…And in acute myeloid leukemia (AML), Zalmai et al. identified a group of pDC-AML with completely different phenotype from BPDCN, with high expression of CD34 and CD303, low expression of CD123 and cTCL1, and no expression of CD56 ( 119 ). Molecular analysis indicated that these pDCs were inactive and neoplastic, and exhibited frequent RUNX1 mutations ( 119 ).…”

“…identified a group of pDC-AML with completely different phenotype from BPDCN, with high expression of CD34 and CD303, low expression of CD123 and cTCL1, and no expression of CD56 ( 119 ). Molecular analysis indicated that these pDCs were inactive and neoplastic, and exhibited frequent RUNX1 mutations ( 119 ). Moreover, studies showed that clinical use of tagraxofusp (SL-401) completely inhibited protein synthesis leading to cell death of pDCs, which had a positive effect on inhibiting acute transformation in leukemia ( 61 , 118 ).…”