Leukemia is a group of progressive hematologic malignancies derived from stem cells in
bone marrow which causes a large number of cancer deaths. Even with treatment such as traditional
chemotherapy, targeted therapy, and allogeneic stem cell transplantation (allo-HSCT), many
patients suffer from relapse/refractory disease, and the overall survival is dismal. Leukemic stem
cells (LSCs) are induced by gene mutations and undergo an aberrant and poorly regulated
proliferation process which is involved in the evolution, relapse, and drug-resistance of leukemia.
Emerging studies demonstrate that CD123, the interleukin 3 receptor alpha (IL-3Rα), is highly
expressed in LSCs, while not normal hematopoietic stem cells (HSCs), and associates with
treatment response, minimal residual disease (MRD) detection and prognosis. Furthermore, CD123
is an important marker for the identification and targeting of LSCs for refractory or relapsed
leukemia. Anti-CD123 target-therapies in pre-clinical studies and clinical trials confirm the utility
of anti-CD123 neutralizing antibody-drugs, CD3×CD123 bispecific antibodies, dual-affinity retargeting
(DART), and anti-CD123 chimeric antigen receptor-modified T-cell (CAR-T) therapies in
progress. This review summarizes the most recent progress on the study of CD123 biology and the
development of novel CD123-targeted therapies.