Immunophenotypic and Molecular Features of Acute Myeloid Leukemia with Plasmacytoid Dendritic Cell Differentiation Are Distinct from Blastic Plasmacytoid Dendritic Cell Neoplasm

Abstract

Acute myeloid leukemia (AML) with ≥2% plasmacytoid dendritic cells (pDC) has been recently described as AML with pDC differentiation (pDC-AML) characterized by pDC expansion with frequent RUNX1 mutations. In this study, we investigated a cohort of 53 pDC-AML cases representing about 3% of all AML cases. We characterized their immunophenotype and genetic profiles and compared these findings with blastic plasmacytoid dendritic cell neoplasm (BPDCN). pDC-differentiation/expansion was preferentially observed in AML with an immature myeloid or myelomonocytic immunophenotype, where myeloblasts were frequently positive for CD34 (98%), CD117 (94%), HLA-DR (100%) and TdT (79%), with increased CD123 (89%) expression. The median number of pDCs in pDC-AML was 6.6% (range, 2% to 26.3%) and their immunophenotype reminiscent of pDCs in early or intermediate stages of differentiation. The immunophenotype of pDCs in pDC-AML was different from BPDCN (n = 39), with major disparities in CD34 (96% vs. 0%), CD56 (8% vs. 97%) and TCL1 (12% vs. 98%) and significant differences in frequency of CD4, CD13, CD22, CD25, CD36, CD38, CD117 and CD303 expression. At the molecular level, the genetic landscapes of pDC-AML and BPDCN also differ, with RUNX1 mutations detected in 64% of pDC-AML versus 2% of BPDCN. Disparities in TET2 (21% vs. 56%), FLT3 (23% vs. 0%), DNMT3A (32% vs. 10%) and ZRSR2 (2% vs. 16%) (all p < 0.05) were also detected. The distinct immunophenotypic and mutation profiles of pDC-AML and BPDCN indicate that the neoplastic pDCs in pDC-AML and BPDCN derived from different subsets of pDC precursors.

Keywords: BPDCN; acute myeloid leukemia; flow cytometry; immunophenotype; mutation; plasmacytoid dendritic cells.

Figure 1

The morphology and immunophenotype (immunohistochemistry) of pDC-AML. (A). Diffuse infiltrate of blasts with variable size on bone marrow core biopsy. (B). Bone marrow aspirate smear shows two types of cells. One is large with round to slightly irregular nuclei, dispersed chromatin and small to moderate amounts of basophilic cytoplasm, consistent with myeloblasts. Another is smaller and many have dispersed chromatin and cytoplasmic pseudopods, consistent with pDCs. By immunohistochemistry, pDCs are strongly positive for CD123 (C,E) and TCF4 (D,E), and weakly positive for CD34 (F). In contrast, myeloblasts are weakly positive for CD123 (C,E) and TCF4 (D,E) with strong expression of CD34 (F). Both pDCs and myeloblasts are negative for CD56 (G) and TCL1 (H) in this case.

Figure 2

The immunophenotype of pDCs in pDC-AML by flow cytometry. The detailed immunophenotype of 53 cases of pDC-AML is displayed (cases # 1–34, RUNX1 mutated; cases # 35–53, RUNX1 wild type). For the category of positive (dec), CD34 expression was compared to the coexisting myeloblasts; CD38 and CD45 expression was compared to normal/reactive pDCs. Of note, similar to positive category, positive (dec) cases also showed >80% cells being positive.

Figure 3

A representative case of pDC-AML by flow cytometry. Myeloblasts are highlighted in red and pDCs are highlighted in blue.

Figure 4

The maturation pattern of pDCs in a case of pDC-AML. pDCs are brightly positive for CD123 (A) and HLA-DR (D). The earliest pDCs are positive for CD34 (B,C,F,G), CD117 (dim, E), CD38 (bright, B), negative for CD4 (F,H) and CD303 (G,H). As they mature, the expression of CD34, CD38 and CD117 decreases, and the expression of CD4 and CD303 increases (H).

Figure 5

The mutational profile of pDC-AML. Cases # 1–34 with RUNX1 mutation, and cases # 35–53 with wild type RUNX1. The case number in this figure correlates with the case number assigned in Figure 1.