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Researchers have identified a novel mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by bone marrow mesenchymal stem cells in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma leads directly to pro-malignancy signaling.
Specifically, increased PADI2 expression by bone marrow mesenchymal stem cells in patients with MGUS (a benign condition that precedes multiple myeloma) or with multiple myeloma directly induces upregulation of interleukin-6 expression through its enzymatic deimination of histone H3 arginine 26, which leads to acquired resistance to bortezomib – a “highly clinically relevant anti-myeloma drug”– by malignant plasma cells, Gavin McNee, PhD, of the University of Birmingham, England, and colleagues reported (Leukemia. 2017;31[2]:373-81).
The findings, based on transcriptomic analysis of mRNA extracted from bone marrow mesenchymal stem cells cultured from MGUS and multiple myeloma patients and controls, could have implications for therapeutic targeting of PADI2 in MGUS and multiple myeloma, the investigators said.
The findings, in the context of those from prior studies, “highlight the significant similarities between the microenvironment of the bone marrow in MGUS and multiple myeloma, suggesting that transformation of the bone marrow microenvironment is an early event in disease etiology, raising the potential of interfering with this process in order to delay or prevent progression of patients with MGUS to multiple myeloma,” they wrote, adding that the data “further highlight a need to identify those biological determinants in the [bone marrow] that actually contribute to the progression of this disease.”
The investigators concluded that PADI2 may therefore represent a good therapeutic target in MGUS and multiple myeloma patients, which “may act by removing a significant proportion of the supportive signaling required by malignant plasma cells for survival and proliferation.”
The authors were supported by grants from Bloodwise, Cancer Research UK, and the Medical Research Council, They reported having no other disclosures.
Researchers have identified a novel mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by bone marrow mesenchymal stem cells in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma leads directly to pro-malignancy signaling.
Specifically, increased PADI2 expression by bone marrow mesenchymal stem cells in patients with MGUS (a benign condition that precedes multiple myeloma) or with multiple myeloma directly induces upregulation of interleukin-6 expression through its enzymatic deimination of histone H3 arginine 26, which leads to acquired resistance to bortezomib – a “highly clinically relevant anti-myeloma drug”– by malignant plasma cells, Gavin McNee, PhD, of the University of Birmingham, England, and colleagues reported (Leukemia. 2017;31[2]:373-81).
The findings, based on transcriptomic analysis of mRNA extracted from bone marrow mesenchymal stem cells cultured from MGUS and multiple myeloma patients and controls, could have implications for therapeutic targeting of PADI2 in MGUS and multiple myeloma, the investigators said.
The findings, in the context of those from prior studies, “highlight the significant similarities between the microenvironment of the bone marrow in MGUS and multiple myeloma, suggesting that transformation of the bone marrow microenvironment is an early event in disease etiology, raising the potential of interfering with this process in order to delay or prevent progression of patients with MGUS to multiple myeloma,” they wrote, adding that the data “further highlight a need to identify those biological determinants in the [bone marrow] that actually contribute to the progression of this disease.”
The investigators concluded that PADI2 may therefore represent a good therapeutic target in MGUS and multiple myeloma patients, which “may act by removing a significant proportion of the supportive signaling required by malignant plasma cells for survival and proliferation.”
The authors were supported by grants from Bloodwise, Cancer Research UK, and the Medical Research Council, They reported having no other disclosures.
Researchers have identified a novel mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by bone marrow mesenchymal stem cells in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma leads directly to pro-malignancy signaling.
Specifically, increased PADI2 expression by bone marrow mesenchymal stem cells in patients with MGUS (a benign condition that precedes multiple myeloma) or with multiple myeloma directly induces upregulation of interleukin-6 expression through its enzymatic deimination of histone H3 arginine 26, which leads to acquired resistance to bortezomib – a “highly clinically relevant anti-myeloma drug”– by malignant plasma cells, Gavin McNee, PhD, of the University of Birmingham, England, and colleagues reported (Leukemia. 2017;31[2]:373-81).
The findings, based on transcriptomic analysis of mRNA extracted from bone marrow mesenchymal stem cells cultured from MGUS and multiple myeloma patients and controls, could have implications for therapeutic targeting of PADI2 in MGUS and multiple myeloma, the investigators said.
The findings, in the context of those from prior studies, “highlight the significant similarities between the microenvironment of the bone marrow in MGUS and multiple myeloma, suggesting that transformation of the bone marrow microenvironment is an early event in disease etiology, raising the potential of interfering with this process in order to delay or prevent progression of patients with MGUS to multiple myeloma,” they wrote, adding that the data “further highlight a need to identify those biological determinants in the [bone marrow] that actually contribute to the progression of this disease.”
The investigators concluded that PADI2 may therefore represent a good therapeutic target in MGUS and multiple myeloma patients, which “may act by removing a significant proportion of the supportive signaling required by malignant plasma cells for survival and proliferation.”
The authors were supported by grants from Bloodwise, Cancer Research UK, and the Medical Research Council, They reported having no other disclosures.
FROM LEUKEMIA
Key clinical point:
Major finding: Increased PADI2 expression by bone marrow mesenchymal stem cells in patients with MGUS or multiple myeloma directly induces upregulation of interleukin-6 expression through its enzymatic deimination of histone H3 arginine 26, which leads to acquired resistance to bortezomib by malignant plasma cells.
Data source: Transcriptomic analysis of mRNA extracted from bone marrow mesenchymal stem cells cultured from MGUS and multiple myeloma patients and controls.
Disclosures: The authors were supported by grants from Bloodwise, Cancer Research UK, and the Medical Research Council, They reported having no other disclosures.