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Precision medicine in acute myeloid leukemia
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
The leukemia stem cells (LSCs) are characterized by their unlimited self-renewal, repopulating potential and long residence in a quiescent state of G0/G1 phase. LSCs are considered to have a pivotal role in the relapse and refractory of AML. Therefore, new therapeutic strategies to target LSCs with limited toxicity toward the normal hematopoietic population is critical for the ultimate curing of AML. Ongoing research works with natural products like parthenolide (a natural plant extract derived compound) and its derivatives that have the ability to target multiple pathways that regulate the self-renewal, growth, and survival of LSCs point to ways for a possible complete remission in AML (Siveen et al., 2017). AML stem cells are not only in the quiescent phase of the cell cycle (G0) and can be also found in cycling cells. Their frequency increases as a function of chemotherapy and subsequent relapse. The first clearly defined AML stem cells–specific antigen was interleukin-3 receptor α (CD123) within CD34+/CD38− compartment (Jordan et al., 2000). Multiple additional immunophenotypic differences that may distinguish AML stem cells from normal hematopoietic stem cells were subsequently identified and can be used for therapeutic intervention using antibody-based targeting strategies (Table 10.9) (Pollyea and Jordan, 2017).
Blastic Plasmacytoid Dendritic Cell Neoplasms (BPDCN)
Published in Dongyou Liu, Tumors and Cancers, 2017
Alternative therapies under investigation include the use of diphtheria toxin to target IL3 receptors on BPDCN cells for specific apoptosis and the application of surface receptors with immunotoxins (i.e., interleukin-3 receptor alpha) or inhibitors of aberrantly activated survival pathways (i.e., NF-κB).
Immunophenotypic Markers
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
CD123 antigen is an antibody that binds to the α-subunit of the interleukin-3 receptor. CD123 is expressed in AML, ALL, NK cell tumors, and dendritic cell neoplasms [88,89]. CD123+ AML are often positive for FLT3-ITD or NPM1 mutations. It can also be expressed in mature B-cell disorders, such as HCL [88,90]. The expression of CD123 in HCL is bright. The subset of HCL-Vs (~40%) and rare cases of other mature B-cell disorders (including SMLZ, CLL, MCL, and FL) may express CD123, but the expression is usually partial and/or dim [90].
Targeting CD123 in BPDCN: an emerging field
Published in Expert Review of Hematology, 2021
Adam J DiPippo, Nathaniel R Wilson, Naveen Pemmaraju
Interleukin-3 receptor alpha (IL-3Rα), more commonly referred to as CD123 is in the beta common (βc) cytokine family involved in normal hematopoiesis and response to immune threats [48,49]. Other members of this cytokine family include IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF). CD123 is comprised of three extracellular domains, two of which bind to IL-3 and one which acts as a regulator of IL-3 signaling. Upon binding of IL-3, CD123 forms a receptor complex bringing other molecules, such as JAK2, together for downstream signaling [50]. The IL-3/IL-3Rα cytokine family plays a key role in regulation of hematopoietic and immune cell production and can stimulate a variety of cell lines including macrophages, mast cells, and basophils. In this way, CD123 is an integral part of the innate immune response; however, it has other sites of expression most notably on endothelial cells, as will be discussed later in reference to potential off-target toxicity from CD123 targeting agents [51].
Emerging pharmacotherapies for elderly acute myeloid leukemia patients
Published in Expert Review of Hematology, 2020
Xavier Thomas, Mohamed Elhamri, Maël Heiblig
CD123 is the alpha subunit of the interleukin-3 receptor. Its expression on myeloid progenitors is high [162]. Targeting CD123 on leukemic stem cells is one promising approach in AML. Talacotuzumab is an IgG1 monoclonal antibody targeting CD123 preferentially via antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer cells. The SAMBA trial, a phase 2 study, assessed the overall hematological response rate after 3 months of single-agent talacotuzumab treatment in patients failing HMAs (NCT02992860). Talacotuzumab was given IV at a dose of 9 mg/Kg once every 2 weeks for a total of 6 infusions, responders received up to 20 additional infusions. However, results showed limited efficacy of talacotuzumab as single agent [163]. A phase 3 trial combining talatuzumab with decitabine versus decitabine is ongoing (NCT02472145).
Hematopoietic growth factors: the scenario in zebrafish
Published in Growth Factors, 2018
Vahid Pazhakh, Graham J. Lieschke
Gene duplication, not least in part the legacy of a whole genome duplication in the teleost radiation, has left its legacy on the zebrafish genome (Braasch et al., 2016; Postlethwait et al., 1998). While gene duplication can be considered to be an added complexity, it has also provided nature with an opportunity to explore biologically feasible variations that can provide biological insight when they are understood. Diversification processes including gene loss, subfunctionalization and neofunctionalization can eliminate or segregate biological functions between duplicates, or assign new functions to individual duplicates. These processes can create new private single ligand/receptor pairs, or regionally isolate components of promiscuous ligand/receptor groups to achieve highly specific anatomically-localized effects. Amongst model organisms, zebrafish are not unique in the diversity of their HGF ligand/receptor configurations: even between humans and mice, significant differences exist. For example, interleukin-3 receptor structure is more complex in the mouse than human, there being an extra mouse-specific alternative beta subunit (Geijsen et al., 2001; Hara & Miyajima, 1992).