Revealing serum lipidomic characteristics and potential lipid biomarkers in patients with POEMS syndrome

Abstract POEMS syndrome is a rare plasma cell dyscrasia with distinct lipid metabolism abnormalities at disease onset. However, the serum lipidomic characteristics in patients with POEMS syndrome were not investigated. The study performed an untargeted lipidome screening by liquid chromatography‐tandem mass spectrometry (LS‐MS/MS) in the pre‐ and post‐treatment serum of 24 patients with POEMS syndrome, together with the serum of 24 paired healthy controls. Patients with POEMS syndrome had a distinct serum lipid composition compared with healthy controls, and a 3‐lipid model had a predictive accuracy of 93.5% in distinguishing patients and healthy controls consisting of fatty acyl 17‐oxo‐20Z‐hexacosenoic acid, phosphatidylcholine(16:0/18:1(9Z)) and sterol lipid 5b‐pregnanediol. Four lipids including 17‐oxo‐20Z‐hexacosenoic acid (r = 0.423, P = .040) were correlated with risk stratification, and 2 lipids including Cer(d18:0/13:0) were inversely related to serum vascular endothelial growth factor level (r=−0.465, P = .022). Eleven lipids were related to disease activity, including arachidonic acid which was inversely related and lysoPC(20:4) which was positively related. The study indicated a distinct lipid characteristic profile of patients with POEMS syndrome different from healthy controls and identified several lipids that may serve as potential diagnostic markers and monitors of therapeutic efficacy, as well as indicating potential metabolism pathways involved in the pathological process.

previous reports, indicating distinct lipid metabolism abnormalities.
Significantly altered lipid metabolism was reported in a variety of haematological malignancies. A serum lipidomic study on patients with acute myeloid leukaemia and myelodysplastic syndromes showed that the levels of lysomonomethyl glycerophosphocholine could effectively distinguish these patients from healthy controls. 4 A study of the serum lipidome in patients with multiple myeloma demonstrated that serum arachidonic acid levels diminished significantly in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) compared with healthy controls. Supplementation with arachidonic acid by injection in MM mice could induce ferroptosis of MM cells, indicating a new drug target for MM. 5 However, the serum lipidomic characteristics in patients with POEMS syndrome were not investigated. Therefore, we designed this study to describe characteristics of the serum lipidome in patients with POEMS syndrome and to explore potential biomarkers in evaluating disease activity and remission.

| Study design
The study schema is shown in Figure 1. A total of 24 POEMS syndrome patients were enrolled, together with 24 paired healthy controls. The baseline and follow-up serum after at least 1 cycle of treatment was collected. By comparing serum lipid components in serum of patients vs. healthy controls, lipids altered under disease status were identified. Biomarkers contributing the most to the disease status among these lipids and enriched pathways were further identified. Lipids related to VEGF level and risk stratification were screened to identify lipids related to disease activity or possessing a potential prognostic value. Lipids related to treatment remission were identified by comparing serum lipid components in baseline vs.
follow-up serum.

| Patients
We enrolled twenty-four patients with POEMS syndrome newly

| Statistical Analysis
LC-MS/MS data were processed using the software package Xcalibur 3.0. The values of the untargeted lipidomic measurements were normalized to total positive or total negative ion signal. Autoscaling was performed before partial least squares discrimination analysis (PLS-DA) and supporter vector machine (SVM) analysis.

| Patient characteristics
The baseline characteristics for patients are shown in Table 1 The lipid profile and fasting blood glucose of 24 healthy controls were in Table S1.   (Figure 2A; Table S2) Patients and healthy controls could be well separated with two components in a PLS-DA plot.

| Identification of lipid species related to VEGF level and risk stratification
Among 83 lipids significantly altered in patients compared with healthy controls, 2 lipids were also correlated with serum VEGF levels  Figure 3B; Table S5).

| Identification of lipid species related to treatment responses
After at least 1 cycle of treatment, 16  follow-up serum in patients without remission. (Table S6.2).
By directly comparing lipids in follow-up serum from patients with and without CR V /PR V , we found 7 lipids that were significantly TA B L E 2 The pathway enrichment analysis of altered lipids between 24 patients and paired healthy controls by mummichog algorithm and GSEA method

| D ISCUSS I ON
In the present study, we applied untargeted lipidome profiling, which to receptors such as PPARγ to further stimulate transcription of downstream redox-regulating enzymes, modulating fatty acid storage and glucose metabolism. 11 As a common isoform of phosphatidylcholine, PC(16:0/18:1) was reported to serve as the endogenous ligand for the nuclear receptor PPARα in hepatocyte. 12 As a transcription factor regulating the expression of many genes that govern lipid metabolism, PPARα is also a drug target for hepatic steatosis. 13 Secondly, we performed a correlation analysis between serum lipids and baseline VEGF and risk stratification. Lipids inversely correlated with serum VEGF levels included Cer(d18:0/13:0), which was also lower in baseline serum of patients vs. healthy controls.
Ceramide was reported to have a proapoptotic effect in the patho- and decreased after remission, paralleled with disease activity. As lysophosphatidylcholine was reported to mediate demyelination and pericyte loss in brain, it may play a role in peripheral neuropathy resulting from demyelination of peripheral nerves in POEMS syndrome. 16,17 Besides, the value of the other 9 lipids related to disease activity on disease activity monitoring should be validated in larger cohorts.
We conducted an untargeted lipidome screening of the serum of patients with POEMS syndrome. Our study indicated a distinct lipid characteristic profile of patients with POEMS syndrome different from healthy controls and identified several lipids that may serve as potential diagnostic markers and monitors of therapeutic efficacy, as well as indicating potential metabolism pathways involved in the pathological process.