In these studies, the BRD4CMYC axis and the JAK-STAT pathway have been identified as major drivers of PD-L1 expression [61,117,118]. article, we provide an overview of the immunologically relevant molecular targets expressed on LSC in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). In addition, we discuss the current status of antibody-based therapies in these malignancies, their mode of action, and successful examples from the field. Keywords: AML, CML, leukemic stem cells, CAR-T cell therapy, bispecific antibodies, precision medicine 1. Introduction Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) are stem cell-derived, life-threatening, LY2140023 (LY404039) hematopoietic neoplasms that are characterized by an uncontrolled expansion of myeloid progenitor cells exhibiting a more or less severe maturation defect. The clinical course, prognosis, and progression patterns vary among patients, depending on the genetic background, age, the sub-type and phase of the disease, cytogenetic and molecular features, and the patients response to initial anti-leukemic (induction) therapy [1,2,3,4,5,6,7,8]. Whereas in CML the disease is characterized by the pathognomonic oncogene, the molecular landscapes in AML are complex and involve several LY2140023 (LY404039) different oncogenes and a plethora of somatic mutations [4,5,6,7,8,9]. By applying intensive chemotherapy and oncogenic driver-specific drugs in AML and BCR-ABL1-targeting compounds in CML, a majority of all patients achieve remission, and in many cases, long-term disease-free survival is achieved [1,2,3,4,5,10,11,12,13]. However, not all patients have a good Rabbit Polyclonal to SNIP response to such therapy, or they relapse after having achieved remission. In patients with multi-resistant disease, hematopoietic stem cell transplantation (HSCT) is usually recommended, but the procedure can only be performed in a limited number of young and fit patients, and carries an inherent mortality risk. As a result, research in AML is currently focusing on new molecular targets and the establishment of more potent drug therapies, including targeted medicines and immunotherapies. The basic theory of leukemic stem cells (LSC) has been created with the intention to explain cellular and molecular hierarchies and to LY2140023 (LY404039) improve anti-neoplastic treatment through the eradication of disease-initiating and disease-propagating cells [14,15,16,17,18,19,20,21,22]. The concept of LY2140023 (LY404039) LSC is based on the hypothesis the leukemic clone and sub-clonal development are organized inside a cellular hierarchy, with (a) more mature leukemic cells that disappear (through apoptosis) after a certain quantity of cell divisions, and (b) LSC that can augment the bulk human population of leukemic cells indefinitely by their unrestricted (unlimited) self-renewing and long-term proliferative capabilities [14,15,16,17,18,19,20,21,22]. In the chronic phase of BCR-ABL1+ CML and in some AML variants, LSC were reported to reside inside a CD34+/CD38? subset of the leukemic clone [14,15,16,17,18,19,20]. However, depending on the molecular background and the phase of the disease, at least some LSC may also be recognized within a CD34+/CD38+ subset of leukemic cells, or sometimes actually inside LY2140023 (LY404039) a CD34-bad cell human population [23,24,25]. Based on their disease-initiating and disease-propagating capacity, LSC are regarded as a major, clinically relevant restorative cell target, and numerous studies have been carried out with the goal of identifying fresh molecular focuses on in these cells [17,18,19,20,21,22,26,27,28,29]. Of unique interest are specific cell surface antigens that can be employed to develop disease-eradicating immunotherapies such as antibody-based or CAR-T cell therapies. However, only a few clinically relevant cell surface focuses on that are indicated specifically on LSC, but not on normal bone marrow (BM) stem cells, have been identified. In the current article, we review the cell surface antigens that are indicated preferentially and even specifically on LSC in AML and/or CML, and thus represent potential focuses on for immunotherapies. In addition, we provide an overview of treatment ideas that have been or are currently being developed based on antigen manifestation and function in leukemic (stem) cells. Moreover, we discuss the current status of antibody-based therapies in AML. Finally, we discuss long term developments in the field, and how LSC-targeting immunotherapies can be translated into medical software. 2. Phenotype of LSC in AML and CML The classical approach to demonstrate self-renewing and long-term disease-propagating capabilities of LSC in vivo is definitely to transplant leukemic cells into immunocompromised mice. Earlier studies employed severe.