Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia.

Abstract

Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcγRIIb, CD32b) for being critical in LSC resistance and show that targeting FcγRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcγRIIb upregulation in primary CML stem cells. FcγRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcγRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcγRIIb-BTK axis in primary CML CD34+ cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition.

• Authors: Oliver Parting, Samantha Langer, Maja Kim Kuepper, Caroline Wessling, Shaoguang Li, Till Braunschweig, Nicolas Chatain, Tiago Maié, Ivan G Costa, Martina Crysandt, Michael Huber, Tim H Brümmendorf, Steffen Koschmieder, Mirle Schemionek
• Journal: Leukemia (Leukemia) Vol. 34 Issue 10 Pg. 2635-2647 (10 2020) ISSN: 1476-5551 [Electronic] England
• PMID: 32684632 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• FCGR2B protein, human
• Protein Kinase Inhibitors
• Receptors, IgG
• Agammaglobulinaemia Tyrosine Kinase
• BTK protein, human
• Fusion Proteins, bcr-abl

Topics

• Agammaglobulinaemia Tyrosine Kinase (antagonists & inhibitors)
• Animals
• Antineoplastic Agents (pharmacology)
• Fusion Proteins, bcr-abl (antagonists & inhibitors)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Neoplastic Stem Cells (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Receptors, IgG (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)