Impact of CD123 expression, analyzed by immunohistochemistry, on clinical outcomes in patients with acute myeloid leukemia

Arai, Nana; Homma, Mayumi; Abe, Maasa; Baba, Yuta; Murai, So; Watanuki, Megumi; Kawaguchi, Yukiko; Fujiwara, Shun; Kabasawa, Nobuyuki; Tsukamoto, Hiroyuki; Uto, Yui; Ariizumi, Hirotsugu; Yanagisawa, Kouji; Hattori, Norimichi; Saito, Bungo; Shiozawa, Eisuke; Harada, Hiroshi; Yamochi-Onizuka, Toshiko; Nakamaki, Tsuyoshi; Takimoto, Masafumi

doi:10.1007/s12185-019-02616-y

Cited by 18 publications

(18 citation statements)

References 28 publications

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“…IL-3 has seen most study in hematologic malignancies 8 , 9 . However, the observation that tumor-infiltrating lymphocytes (TILs) 10 and TEC are able to produce IL-3 11 , sustains the possibility that IL-3 can also control the tumor microenvironment (TME).…”

Section: Introductionmentioning

confidence: 99%

Targeting IL-3Rα on tumor-derived endothelial cells blunts metastatic spread of triple-negative breast cancer via extracellular vesicle reprogramming

et al. 2020

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The lack of approved targeted therapies highlights the need for new treatments for triple-negative breast cancer (TNBC) patients. Interleukin-3 (IL-3) acts as an autocrine factor for tumor–endothelial cells (TEC), and exerts pro-angiogenic paracrine action via extracellular vesicles (EVs). IL-3Rα blockade on TEC changes TEC-EV (anti-IL-3R-EV) microRNA (miR) content and promotes the regression of established vessels. As TEC is the doorway for “drug” entry into tumors, we aimed to assess whether IL-3R blockade on TEC impacts tumor progression via its unique EV cargo. First, the expression of IL-3Rα was evaluated in 27 human TNBC samples. It was noticed that, besides TEC and inflammatory cells, tumor cells from 55.5% of the human TNBC samples expressed IL-3Rα. Using human TNBC cell lines for in vitro studies, we found that, unlike native TEC-EVs (nEVs), anti-IL-3R-EVs increase apoptosis and reduced cell viability and migration. In vivo, anti-IL-3R-EV treatment induced vessel regression in established tumors formed of MDA-MB-231 cells, decreased Vimentin, β-catenin, and TWIST1 expression, almost abolished liver and lung metastases from primary tumors, and reduced lung metastasis generated via the intravenous injection of MDA-MB-231 cells. nEVs depleted of miR-24-3p (antago-miR-24-3p-EVs) were effective as anti-IL-3R-EVs in downregulating TWIST1 and reducing metastatic lesions in vivo. Consistent with network analyses of miR-24-3p gene targeting, anti-IL-3R-EVs and antago-miR-24-3p-EVs upregulate SPRY2 in MDA-MB-231 cells. Finally, SPRY2 silencing prevented anti-IL-3R-EV and antago-miR-24-3p-EV-mediated apoptotic cues. Overall, these data provide the first evidence that IL-3Rα is highly expressed in TNBC cells, TEC, and inflammatory cells, and that IL-3Rα blockade on TEC impacts tumor progression.

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Section: Introductionmentioning

confidence: 99%

Targeting IL-3Rα on tumor-derived endothelial cells blunts metastatic spread of triple-negative breast cancer via extracellular vesicle reprogramming

et al. 2020

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“…Arai and coworkers have explored CD123 expression on 48 de novo AMLs by immunohistochemistry and reported that CD123 expression on AML blasts was associated with a failure to achieve a complete response to initial induction chemotherapy and poor overall survival [52].…”

Section: Introductionmentioning

confidence: 99%

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

Testa

Pelosi

Castelli

2019

Cancers

103

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The interleukin-3 receptor alpha chain (IL-3Rα), more commonly referred to as CD123, is widely overexpressed in various hematological malignancies, including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, hairy cell leukemia, Hodgkin lymphoma and particularly, blastic plasmacytoid dendritic neoplasm (BPDCN). Importantly, CD123 is expressed at both the level of leukemic stem cells (LSCs) and more differentiated leukemic blasts, which makes CD123 an attractive therapeutic target. Various agents have been developed as drugs able to target CD123 on malignant leukemic cells and on the normal counterpart. Tagraxofusp (SL401, Stemline Therapeutics), a recombinant protein composed of a truncated diphtheria toxin payload fused to IL-3, was approved for use in patients with BPDCN in December of 2018 and showed some clinical activity in AML. Different monoclonal antibodies directed against CD123 are under evaluation as antileukemic drugs, showing promising results either for the treatment of AML minimal residual disease or of relapsing/refractory AML or BPDCN. Finally, recent studies are exploring T cell expressing CD123 chimeric antigen receptor-modified T-cells (CAR T) as a new immunotherapy for the treatment of refractory/relapsing AML and BPDCN. In December of 2018, MB-102 CD123 CAR T developed by Mustang Bio Inc. received the Orphan Drug Designation for the treatment of BPDCN. In conclusion, these recent studies strongly support CD123 as an important therapeutic target for the treatment of BPDCN, while a possible in the treatment of AML and other hematological malignancies will have to be evaluated by in the ongoing clinical studies.

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“…366 Its expression on normal hematopoietic cells has been characterized as low to absent and it has been identified as a unique marker on both on LSCs and AML bulk cells, making it an appropriate target for immunotherapies. 367 CD123 expression is correlated with failure to achieve remission and worse overall prognosis 368,369 and thus has been extensively studied as an immunotherapeutic target in AML. Further studies have identified overlap in overexpression of CD123 in patients who also have FLT3-ITD-and NPM1-mutated AMLs.…”

Section: Targeting Signaling Pathways In Lscsmentioning

confidence: 99%

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

Carter

Hege

Yang

et al. 2020

Sig Transduct Target Ther

114

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Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.

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Impact of CD123 expression, analyzed by immunohistochemistry, on clinical outcomes in patients with acute myeloid leukemia

Cited by 18 publications

References 28 publications

Targeting IL-3Rα on tumor-derived endothelial cells blunts metastatic spread of triple-negative breast cancer via extracellular vesicle reprogramming

Targeting IL-3Rα on tumor-derived endothelial cells blunts metastatic spread of triple-negative breast cancer via extracellular vesicle reprogramming

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

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