Waldenström Macroglobulinemia and Non-IgM-Type Lymphoplasmacytic Lymphoma Are Genetically Similar.

INTRODUCTION: Waldenström macroglobulinemia (WM) represents a subset of lymphoplasmacytic lymphoma (LPL) with the immunoglobulin (Ig)M paraprotein. MYD88 L265P and CXCR4 mutations are common mutations in WM patients, and mutations in ARID1A and KMT2D (MLL2) have also been reported. However, little information has been accumulated on genetic changes in LPL with other paraproteins like IgG. METHODS: We therefore aimed to evaluate genetic differences between WM and LPL with non-IgM paraprotein (non-IgM-type LPL) using targeted next-generation sequencing (NGS) in 20 Japanese patients (10 with WM, 10 with non-IgM-type LPL). RESULTS: Mutations were detected in ARID1A (10%), CXCR4 (20%), MYD88 (90%), and KMT2D (0%) for WM patients and in ARID1A (10%), CXCR4 (20%), MYD88 (70%), and KMT2D (10%) for non-IgM-type LPL patients. No significant differences were identified. No mutations were detected in NOTCH2, PRDM1, CD274 (PD-L1), PDCD1LG2 (PD-L2), RAG2, MYBBP1A, TP53, or CD79B. DISCUSSION: Mutant allele frequency in MYD88 L265P did not differ significantly between WM and non-IgM-type LPL. Most mutations detected by NGS were subclonal following MYD88 L265P, although one non-IgM-type LPL patient harbored only CXCR4 S338X mutation. Our NGS analyses reveal genetic characteristics in LPL patients and suggest genetic similarities between these two subsets of LPL, WM and non-IgM-type.

Sub-lethal doses of chemotherapeutic agents induce senescence in T cells and upregulation of PD-1 expression.

Cellular senescence is a stable cell cycle arrest, usually in response to internal and/or external stress, including telomere dysfunction, abnormal cellular growth, and DNA damage. Several chemotherapeutic drugs, such as melphalan (MEL) and doxorubicin (DXR), induce cellular senescence in cancer cells. However, it is not clear whether these drugs induce senescence in immune cells. We evaluated the induction of cellular senescence in T cells were derived from human peripheral blood mononuclear cells (PBMNCs) in healthy donors using sub-lethal doses of chemotherapeutic agents. The PBMNCs were kept overnight in RPMI 1640 medium with 2% phytohemagglutinin and 10% fetal bovine serum and then cultured in RPMI 1640 with 20 ng/mL IL-2 and sub-lethal doses of chemotherapeutic drugs (2 µM MEL and 50 nM DXR) for 48 h. Sub-lethal doses of chemotherapeutic agents induced phenotypes associated with senescence, such as the formation of γH2AX nuclear foci, cell proliferation arrest, and induction of senescence-associated beta-galactosidase (SA-ß-Gal) activity, (control vs. MEL, DXR; median mean fluorescence intensity (MFI) 1883 (1130-2163) vs. 2233 (1385-2254), 2406.5 (1377-3119), respectively) in T cells. IL6 and SPP1 mRNA, which are senescence-associated secretory phenotype (SASP) factors, were significantly upregulated by sublethal doses of MEL and DXR compared to the control (P = 0.043 and 0.018, respectively). Moreover, sub-lethal doses of chemotherapeutic agents significantly enhanced the expression of programmed death 1 (PD-1) on CD3 + CD4 + and CD3 + CD8 + T cells compared to the control (CD4 + T cells; P = 0.043, 0.043, and 0.043, respectively, CD8 + T cells; P = 0.043, 0.043, and 0.043, respectively). Our results suggest that sub-lethal doses of chemotherapeutic agents induce senescence in T cells and tumor immunosuppression by upregulating PD-1 expression on T cells.

IDO2 rs10109853 polymorphism affects the susceptibility to multiple myeloma.

Single-nucleotide polymorphisms (SNPs) of the IDO1 and IDO2 genes have been associated with some diseases. Here, we investigated the association of IDO1 and IDO2 SNPs with the susceptibility to multiple myeloma (MM) and their relationships with MM clinical features. We obtained genomic DNA from 100 patients with MM and 149 healthy race-matched controls and determined IDO1 promoter - 1849G/T (rs3824259) and IDO2 R248W (rs10109853) genotypes by using the polymerase chain reaction-restriction fragment length polymorphism method. The patients with MM had a significantly higher frequency of the IDO2 R248W RR genotype (high-activity type) (59.0% vs. 43.6%, odds ratio = 1.86, 95% confidence interval = 1.11-3.11, P = 0.017) compared with those in healthy controls. Patients with the IDO2 R248W RR genotype (high-activity type) were significantly younger and had a significantly lower frequency of International Staging System (ISS) stage III condition than those with the RW and WW genotypes (median 63 years vs. 69 years, P = 0.025; 15 [25.4%] vs. 50 [48.8%]). In addition, the IDO2 R248W RR genotype was significantly associated with a higher level of hemoglobin at diagnosis (mean ± standard deviation, 10.7 ± 2.36 vs. 9.27 ± 2.40 g/dL; P = 0.0032). Neither polymorphism significantly affected overall survival. Our study indicates that IDO2 R248W may be associated with the susceptibility to MM and severity of anemia.