Key Points

  • Expression of target molecules for immunotherapy in pediatric AML differs from expression profiles in adult AML

  • CD33/CLEC12A are preferential generic combinatorial immunotargets in pediatric AML and CD33/FLT3 specifically for KMT2A-mutated infant AML

Emerging immunotherapies such as chimeric antigen receptor T cells have advanced the treatment of acute lymphoblastic leukemia. In contrast, long-term control of acute myeloid leukemia (AML) cannot be achieved by single lineage-specific targeting while sparing benign hematopoiesis. In addition, heterogeneity of AML warrants combinatorial targeting and several suitable immunotargets (HAVCR2/CD33 or HAVCR2/CLEC12A) were identified in adult AML. However, clinical and biologic characteristics differ between children and the elderly. Here, we analyzed 36 bone marrow (BM) samples of pediatric AML patients and 13 age-matched healthy donors using whole RNA-sequencing of sorted CD45dim and CD34+CD38-CD45dim BM populations and flow cytometry for surface expression of putative target antigens. Pediatric AML clusters apart from healthy myeloid BM precursors in principle component analysis. Immunotargets known from adult AML such as IL3RA were not overexpressed in pediatric AML compared to healthy precursors by RNA-sequencing. CD33 and CLEC12A were the most upregulated immunotargets on RNA level and showed the highest surface expression on AML detected by flow cytometry. KMT2A mutated infant AML cluster separately by RNA-sequencing, overexpress FLT3 and hence CD33/FLT3 co-targeting is an additional specific option for this subgroup. CLEC12A and CD33/CLEC12Adouble-positive expression was absent in CD34+CD38-CD45RA-CD90+ hematopoietic stem cells (HSC) and both are restricted to healthy hematopoietic tissue, while CD33 and FLT3 is expressed on HSC. In summary, we show that expression of immunotargets in pediatric AML differs from known expression profiles in adult AML. We identify CLEC12A/CD33 as preferential generic combinatorial immunotargets in pediatric AML and CD33/FLT3 as immunotargets specific for KMT2A mutated infant AML.

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