CXCR4 in Waldenström's Macroglobulinema: chances and challenges

Abstract

It is one of the major aims in cancer research to improve our understanding of the underlying mechanisms which initiate and maintain tumor growth and to translate these findings into novel clinical diagnostic and therapeutic concepts with the ultimate goal to improve patient care. One of the greater success stories in this respect has been Waldenström's Macroglobulinemia (WM), which is an incurable B-cell neoplasm characterized by serum monoclonal immunoglobulin M (IgM) and clonal lymphoplasmacytic cells infiltrating the bone marrow. Recent years have succeeded to describe the molecular landscape of WM in detail, highlighting two recurrently mutated genes, the MYD88 and the CXCR4 genes: MYD88 with an almost constant and recurrent point mutation present in over 90% of patients and CXCR4 with over 40 different mutations in the coding region affecting up to 40% of patients. Intriguingly, both mutations are activating mutations leading in the case of CXCR4 to an indelible activation and perpetual signaling of the chemokine receptor. These data have shed light on the essential role of CXCR4 in this disease and have paved the way to use these findings for predicting treatment response to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and novel therapeutic approaches in WM, which might be transferable to other related CXCR4 positive diseases. Well known for its central role in cancer progression and distribution, CXCR4 is highlighted in this review with regard to its biology, prognostic and predictive relevance and therapeutic implications in WM.

Fig. 1. Schematic overview of CXCR4 signaling.

Pathways involved in CXCR4 CXCL12/CXCR4 signaling pathways. AKT protein kinase B, PI3K phosphatidylinositol 3-kinase, NFkB nuclear factor kappa-light-chain-enhancer of activated B cells, FOXO forkhead box, FAK focal adhesion kinase, Pyk-2 proline-rich kinase-2, CRK Adapter molecule crk, Rho Ras homolog gene family, Rac Ras-related C3 botulinum toxin substrate, CDC42 cell division control protein 42 homolog, JAK janus kinase, STATsignal transducer and activator of transcription, cAMP cyclic adenosine monophosphate, PKA protein kinase A, Ras rat sarcoma protein family, RAF proto-oncogene serine/threonine-protein kinase, MEK dual specificity mitogen-activated protein kinase, ERK extracellular-signal-regulated kinase, PIP2 phosphatidylinositol bisphosphate, PLC phospholipase C, PKC protein kinase C, IP₃ inositol trisphosphate, DAG diacylglycerol, ER endoplasmic reticulum, MAPK mitogen-activated protein kinase, Ca²⁺ Calcium ions, CXCR4 C-X-C chemokine receptor type 4, CXCL12 C-X-C chemokine ligand 12.

Fig. 2. MYD88 and CXCR4 mutations in WM.

Summary of the distribution of MYD88 and CXCR4 mutations in WM (according to [58, 68, 76, 77]). MRR are given for Ibrutinib (for MYD88^L265P / CXCR4^WT, MYD88^WT / CXCR4^WT according to [76, 77] (n = 62) and for CXCR4 FS (n = 49) versus NS (n = 19) according to [68]) NS nonsense, FS frameshift, WT wildtype WHIM Warts, Hypogammaglobulinemia, recurrent bacterial Infections and Myelokathexis, MRR major responds rate.

Fig. 3. Progression-free survival of WM patients treated with ibrutinib/rituximab versus placebo/rituximab.

The iNNOVATE phase III randomized study (a) for the total patient group and (b) depending on the MYD88/CXCR4 mutational status [108].

Fig. 4. Summary of the generation, interaction, and function of the CXCR4 antagonist EPI-X4.

The endogenous peptide EPI-X4 is cleaved from highly abundant serum albumin under low pH conditions. The generation is controlled by aspartatic proteases Cathepsin D and E and stopped by leucylaminpeptidases (LAPs) within a relatively short time-frame. After its release EPI-X4 binds to CXCR4 in a very specific manner and competes with CXCL12 binding, acting as an antagonist. Its inverse agonist ability furthermore suppresses constitutive signaling activity of CXCR4 in the absence of CXCL12. By cordoning off the interaction between CXCR4 and its agonist CXCL12, EPI-X4 mobilizes hematopoietic stem cells and is able to suppress migration and homing of cancer cells.