Open AccessCD 300f epitopes are specific targets for acute myeloid leukemia with monocytic differentiation
Author(s) -
Abadir Edward,
Gasiorowski Robin E.,
Lai Kaitao,
Kupresanin Fiona,
Romano Adelina,
Silveira Pablo A.,
Lo TsunHo,
Fromm Phillip D.,
Kennerson Marina L.,
Iland Harry J.,
Ho P. Joy,
Hogarth P. Mark,
Bradstock Kenneth,
Hart Derek N.J.,
Clark Georgina J.
Publication year - 2019
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12549
Subject(s) - epitope , haematopoiesis , myeloid leukemia , myeloid , monoclonal antibody , antibody , biology , stem cell , gene isoform , microbiology and biotechnology , leukemia , cancer research , immunology , gene , genetics
Antibody‐based therapy in acute myeloid leukemia ( AML ) has been marred by significant hematologic toxicity due to targeting of both hematopoietic stem and progenitor cells ( HSPC s). Achieving greater success with therapeutic antibodies requires careful characterization of the potential target molecules on AML . One potential target is CD 300f, which is an immunoregulatory molecule expressed predominantly on myeloid lineage cells. To confirm the value of CD 300f as a leukemic target, we showed that CD 300f antibodies bind to AML from 85% of patient samples. While one CD 300f monoclonal antibody ( mA b) reportedly did not bind healthy hematopoietic stem cells, transcriptomic analysis found that CD 300f transcripts are expressed by healthy HSPC . Several CD 300f protein isoforms exist as a result of alternative splicing. Importantly for antibody targeting, the extracellular region of CD 300f can be present with or without the exon 4‐encoded sequence. This results in CD 300f isoforms that are differentially bound by CD 300f‐specific antibodies. Furthermore, binding of one mA b, DCR ‐2, to CD 300f exposes a structural epitope recognized by a second CD 300f mA b, UP ‐D2. Detailed analysis of publicly available transcriptomic data indicated that CD 34 + HSPC expressed fewer CD 300f transcripts that lacked exon 4 compared to AML with monocytic differentiation. Analysis of a small cohort of AML cells revealed that the UP ‐D2 conformational binding site could be induced in cells from AML patients with monocytic differentiation but not those from other AML or HSPC . This provides the opportunity to develop an antibody‐based strategy to target AML s with monocytic differentiation but not healthy CD 34 + HSPC s. This would be a major step forward in developing effective anti‐ AML therapeutic antibodies with reduced hematologic toxicity.