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In Vivo Assessment of Glutamine Anaplerosis into the TCA Cycle in Human Pre-malignant and Malignant Clonal Plasma Cells
Wilson Gonsalves
Mayo Clinic Rochester: Mayo Clinic Minnesota
Corresponding Author
ORCiD: https://orcid.org/0000-0001-6890-969X
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Cancer & Metabolism.
Background
Overexpression of c-Myc is required for the progression of pre-malignant plasma cells in monoclonal gammopathy of undetermined significance (MGUS) to malignant plasma cells in multiple myeloma (MM). c-Myc also increases glutamine anaplerosis into the tricarboxylic acid (TCA) cycle within cancer cells. Whether increased glutamine anaplerosis is associated with the progression of pre-malignant to malignant plasma cells is unknown.
Methods
Human volunteers (N = 7) and patients with MGUS (N = 11) and MM (N = 12) were prospectively recruited to undergo an intravenous infusion of 13C-labelled glutamine followed by a bone marrow aspiration to obtain bone marrow cells and plasma.
Results
Despite notable heterogeneity, stable isotope resolved metabolomics (SIRM) revealed that the mean 13C-labelled glutamine anaplerosis into the TCA cycle was higher in malignant compared to pre-malignant bone marrow plasma cells relative to the remainder of their paired bone marrow mononuclear cells. RNA sequencing demonstrated a higher relative mRNA expression of c-Myc and glutamine transporters such as ASCT2 and SN2 in malignant compared to pre-malignant bone marrow plasma cells. Finally, higher quantitative levels of TCA cycle intermediates in the bone marrow plasma differentiated MM from MGUS patients.
Conclusion
Measurement of the in vivo activity of glutamine anaplerosis into the TCA cycle provides novel insight into the metabolic changes associated with the transformation of pre-malignant plasma cells in MGUS to malignant plasma cells in MM.
Keywords
stable isotope metabolomics, plasma cell malignancies, myeloma, glutamine
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CURRENT STATUS: Published
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Posted 22 Oct, 2020
Published
On 11 Dec, 2020
No community comments so far
Editorial decision: Major revision
On 30 Oct, 2020
Review #1 received
Received 28 Oct, 2020
Reviewers invited
Invitations sent on 13 Oct, 2020
Reviewer #1 agreed
On 13 Oct, 2020
First submitted
On 12 Oct, 2020
Editor assigned
On 12 Oct, 2020
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On 11 Oct, 2020
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This preprint is under consideration at Cancer & Metabolism. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
In Vivo Assessment of Glutamine Anaplerosis into the TCA Cycle in Human Pre-malignant and Malignant Clonal Plasma Cells
Wilson Gonsalves
Mayo Clinic Rochester: Mayo Clinic Minnesota
Corresponding Author
ORCiD: https://orcid.org/0000-0001-6890-969X
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 1
Posted 22 Oct, 2020
Published
On 11 Dec, 2020
No community comments so far
Editorial decision: Major revision
On 30 Oct, 2020
Review #1 received
Received 28 Oct, 2020
Reviewers invited
Invitations sent on 13 Oct, 2020
Reviewer #1 agreed
On 13 Oct, 2020
First submitted
On 12 Oct, 2020
Editor assigned
On 12 Oct, 2020
Submission checks complete
On 11 Oct, 2020
Editor invited
On 11 Oct, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Cancer & Metabolism.
Background
Overexpression of c-Myc is required for the progression of pre-malignant plasma cells in monoclonal gammopathy of undetermined significance (MGUS) to malignant plasma cells in multiple myeloma (MM). c-Myc also increases glutamine anaplerosis into the tricarboxylic acid (TCA) cycle within cancer cells. Whether increased glutamine anaplerosis is associated with the progression of pre-malignant to malignant plasma cells is unknown.
Methods
Human volunteers (N = 7) and patients with MGUS (N = 11) and MM (N = 12) were prospectively recruited to undergo an intravenous infusion of 13C-labelled glutamine followed by a bone marrow aspiration to obtain bone marrow cells and plasma.
Results
Despite notable heterogeneity, stable isotope resolved metabolomics (SIRM) revealed that the mean 13C-labelled glutamine anaplerosis into the TCA cycle was higher in malignant compared to pre-malignant bone marrow plasma cells relative to the remainder of their paired bone marrow mononuclear cells. RNA sequencing demonstrated a higher relative mRNA expression of c-Myc and glutamine transporters such as ASCT2 and SN2 in malignant compared to pre-malignant bone marrow plasma cells. Finally, higher quantitative levels of TCA cycle intermediates in the bone marrow plasma differentiated MM from MGUS patients.
Conclusion
Measurement of the in vivo activity of glutamine anaplerosis into the TCA cycle provides novel insight into the metabolic changes associated with the transformation of pre-malignant plasma cells in MGUS to malignant plasma cells in MM.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the manuscript can be downloaded and accessed as a PDF.