Endoglin: a novel target for therapeutic intervention in acute leukemias revealed in xenograft mouse models

Abstract

• Leukemia-forming activity is enriched in endoglinexpressing AML and B-ALL blasts using a mouse xenograft model. • Inhibition of endoglin function with TRC105 reduces leukemia development and progression.Endoglin (CD105), a receptor of the transforming growth factor-b superfamily, has been reported to identify functional long-term repopulating hematopoietic stem cells, and has been detected in certain subtypes of acute leukemias. Whether this receptor plays a functional role in leukemogenesis remains unknown. We identified endoglin expression on the majority of blasts from patients with acute myeloid leukemia (AML) and acute B-lymphoblastic leukemia (B-ALL). Using a xenograft model, we find that CD105 1 blasts are endowed with superior leukemogenic activity compared with the CD105 2 population.We test the effect of targeting this receptor using the monoclonal antibody TRC105, and find that in AML, TRC105 prevented the engraftment of primary AML blasts and inhibited leukemia progression following disease establishment, but in B-ALL, TRC105 alone was ineffective due to the shedding of soluble CD105. However, in both B-ALL and AML, TRC105 synergized with reduced intensity myeloablation to inhibit leukemogenesis, indicating that TRC105 may represent a novel therapeutic option for B-ALL and AML. (Blood. 2017;129(18):2526-2536

Serial transplantation reveals a critical role for endoglin in hematopoietic stem cell quiescence

“…Nevertheless, we and other investigators have observed that this receptor is expressed in the HSC of every hematopoietic site, including the aorta-gonad-mesonephros, 19,20 the fetal liver, 21 and the adult BM. 22 In BM, Eng has been shown to selectively mark the LT-HSCs in mice 22,23 and humans; [24][25][26] however, it remains unknown whether this receptor is required for HSC function.…”

Endoglin (CD105) expression in neurofibromatosis type 2 vestibular schwannoma

“…The goals of treatment are to prevent further cranial nerve morbidity and preserve hearing function. 11,25 Considering patients with advanced solid tumors, Gordon et al 27 reported that TRC105 was well tolerated with bevacizumab, and clinical activity was observed in a population refractory to VEGF inhibitors: this could have clinical implications for NF2-associated VSs too. Measuring protein secretion is a convenient way to assess the biological activity of tumor cells.…”

“…It inhibits angiogenesis and tumor growth by endothelial cells growth inhibition, antibody-dependent cellular cytotoxicity, inhibition of signal transduction and/or aberrant signal transduction, induction of apoptosis, and complementing VEGF inhibitors. 11,25 Considering patients with advanced solid tumors, Gordon et al 27 reported that TRC105 was well tolerated with bevacizumab, and clinical activity was observed in a population refractory to VEGF inhibitors: this could have clinical implications for NF2-associated VSs too.…”

“…9 The angiogenic process includes cell migration, proliferation, microvessel differentiation and anastomosis, extracellular matrix degradation, and structural reorganization. 11,12 Antibodies against CD105 react preferentially with active endothelial cells of angiogenic tissues, and it has emerged that using CD105 staining to assess neovascularization has prognostic potential in several solid neoplasms. Assessing tumor angiogenesis demands the application of reliable indicators or markers.…”

“…Endoglin (also known as CD105) is a homodimeric transmembrane glycoprotein and ancillary receptor of the transforming growth factor-b superfamily. 11,12 Antibodies against CD105 react preferentially with active endothelial cells of angiogenic tissues, and it has emerged that using CD105 staining to assess neovascularization has prognostic potential in several solid neoplasms. 10 In a detailed meta-analysis on the association between CD105 expression and prognosis in patients with cancer (30 studies involving 3613 patients), Zhang et al 13 concluded that CD105assessed microvessel density was a predictor of overall survival, disease-free survival, and cancer-specific survival.…”