Targeted positron emission tomography imaging of CXCR4 expression in patients with acute myeloid leukemia

Abstract

A cute myeloid leukemia originates from leukemia-initiating cells that reside in the protective bone marrow niche. CXCR4/CXCL12 interaction is crucially involved in recruitment and retention of leukemia-initiating cells within this niche. Various drugs targeting this pathway have entered clinical trials. To evaluate CXCR4 imaging in acute myeloid leukemia, we first tested CXCR4 expression in patient-derived primary blasts. Flow cytometry revealed that high blast counts in patients with acute myeloid leukemia correlate with high CXCR4 expression. The wide range of CXCR4 surface expression in patients was reflected in cell lines of acute myeloid leukemia. Next, we evaluated the CXCR4-specific peptide Pentixafor by positron emission tomography imaging in mice harboring CXCR4 positive and CXCR4 negative leukemia xenografts, and in 10 patients with active disease. [ 68 Ga]Pentixafor-positron emission tomography showed specific measurable disease in murine CXCR4 positive xenografts, but not when CXCR4 was knocked out with CRISPR/Cas9 gene editing. Five of 10 patients showed tracer uptake correlating well with leukemia infiltration assessed by magnetic resonance imaging. The mean maximal standard uptake value was significantly higher in visually CXCR4 positive patients compared to CXCR4 negative patients. In summary, in vivo molecular CXCR4 imaging by means of positron emission tomography is feasible in acute myeloid leukemia. These data provide a framework for future diagnostic and theranostic approaches targeting the CXCR4/CXCL12-defined leukemia-initiating cell niche.

Side Effects of CXC-Chemokine Receptor 4–Directed Endoradiotherapy with Pentixather Before Hematopoietic Stem Cell Transplantation

“…Because of the successful development of a radiolabeled CXCR4 ligand ( 68 Ga-pentixafor), it is now possible to visualize CXCR4 expression in vivo by means of PET imaging (6,7). Several proof-of-concept studies have shown the potential of the PET tracer 68 Ga-pentixafor to visualize CXCR4-positive tumors, with a specific applicability for patients with hematologic diseases such as non-Hodgkin lymphoma (8), multiple myeloma (9,10), and acute leukemia (11).…”

MDM4 is an essential disease driver targeted by 1q gain in Burkitt lymphoma

“…Animal studies were performed in agreement with the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication n. 85-23, revised 1996), in compliance with the German law on the protection of animals, and with the approval of the regional authorities responsible (Regierung von Oberbayern). The in-vivo experiments were performed as published previously (Herhaus et al, 2016). Briefly, Seraphine-TP53wt, Seraphine-p53ko and Raji cell lines were infected in vitro with shNT or shMDM4 aiming at > 80% transduction efficiency.…”

“…To evaluate the potential of MDM4 as a therapeutic target in TP53wt BL in vivo, we determined the effect of MDM4 silencing on tumor growth in a mouse xenograft model. After transduction, cell lines representing TP53wt (Seraphine), TP53ko (Serphine-TP53ko) and TP53mut (Raji) were injected subcutaneously into the flanks of immunodeficient mice (Herhaus et al, 2016). To quantify tumor formation and dynamic growth, we measured fludeoxyglucose (FDG) uptake in positron emission tomography (PET).…”

MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma

“…85-23, revised 1996), in compliance with the German law on the protection of animals, and with the approval of the regional authorities responsible (Regierung von Oberbayern). The in vivo experiments were performed as published previously (23). Briefly, Seraphine-TP53wt, Seraphine-TP53ko, and Raji cell lines were infected in vitro with shNT or shMDM4 aiming at >80% transduction efficiency.…”

“…To evaluate the potential of MDM4 as a therapeutic target in TP53wt Burkitt lymphoma in vivo, we determined the effect of MDM4 silencing on tumor growth in a mouse xenograft model. After transduction, cell lines representing TP53wt (Seraphine), TP53ko (Seraphine-TP53ko) and TP53mut (Raji) were injected subcutaneously into the flanks of immunodeficient mice (23). To quantify tumor formation and dynamic growth, we measured fludeoxyglucose (FDG) uptake in positron emission tomography (PET).…”