Page 196 - Haematologica Vol. 109 - July 2024

ARTICLE - FLT3L promotes osteolysis in multiple myeloma
D. Shin et al.
all expressed genes using each permuted dataset, and esti- mating a Gaussian kernel density function for the resulting t statistic values. Using the estimated empirical distribution, we computed the adjusted P-values for the observed t sta- tistic value for each gene by performing two-sided testing. Finally, we identified molecular signatures as those that had t test P<0.05 and log2-fold-changes >1.5.
Enrichment analysis of cellular pathways and gene ontology biological processes
To identify cellular processes and pathways represented by the molecular signatures for each patient subtype, we performed the enrichment analysis of pathways and gene ontology biological processes (GOBP) for the selected mo- lecular signatures using ConsensusPathDB.25 The cellular pathways and GOBP represented by the molecular signa- tures for each subtype were selected as those with P<0.05, and the number of molecules involved in the pathway or GOBP ≥3.
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Results
FLT3L reflects osteolytic bone lesion and prognosis in multiple myeloma
FLT3L level was reported to be elevated in BM and blood of patients with MM. To confirm this finding in Korean MM pa- tients, and to further examine the association of FLT3L level with bone osteolytic bone lesion, we collected BM-derived plasma samples from 86, 306, and 52 patients with MM, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL), respectively. FLT3L level of monoclonal gammopa- thy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) was included (N=42), as MGUS/ SMM involves no osteolytic bone lesion.25 Patients’ clinical characteristics are presented in Table 1. FLT3L levels were significantly (P<0.05) elevated in Korean patients with MM (median 161.8 pg/mL, interquartile range [IQR] 73.96-233.50) compared to those in AML (median 28.16, IQR 8.48-107.30) and ALL (median 46.11, IQR 12.52-172.80) (Figure 1A). Consid-
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Figure 1. Plasma expression of Fms-like tyrosine kinase 3 ligand is elevated in multiple myeloma patients. (A) The plasma level of Fms-like tyrosine kinase 3 ligand (FLT3L) in bone marrow (BM) is significantly higher in multiple myeloma (MM) (N=86; median 161.8 pg/mL, interquartile range [IQR] 73.96-233.5) than in acute myeloid leukemia (AML) (N=306; median 28.16, IQR 8.48-107.3), acute lymphoblastic leukemia (ALL) (N=52; median 46.11, IQR 12.52-172.8), and monoclonal gammopathy of undetermined signif- icance (MGUS) / smoldering multiple myeloma (SMM) (N=42). (B) The plasma level of FLT3L in BM of MM shows a linear correlation with the percentage of plasma cell / total nucleated cells in BM aspirates at the time of initial diagnosis (N=43). (C) The plasma level of FLT3L in BM is higher in MM with osteolytic bone lesion (N=27, median 194.70, IQR, 152.52-242.27) than in MM without bone lesion (N=16, median 141.62 pg/mL, IQR, 109.57-215.98) at the time of initial diagnosis (P=0.0047). (D) Kaplan-Meier survival curves for MM patients with low and high FLT3L expression levels. *P<0.05, **P<0.01, ***P<0.001, ns: not significant.
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