Characteristics of Waldenström Macroglobulinemia in Korean Patients According to Mutational Status of MYD88 and CXCR4

Analysis Using Ultra-Deep Sequencing

Dong Woo Shin, Sung Min Kim, Jung Ah Kim, Hee Sue Park, Sang Mee Hwang, Kyongok Im, Sungsik Kim, Jinhyun Kim, Sunghoon Kwon, Sung-Soo Yoon, Dong Soon Lee

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

Background: Little is known about the mutational frequency of myeloid differentiation factor 88 (MYD88) and C-X-C chemokine receptor type 4 (CXCR4) and the corresponding characteristics in Asian individuals afflicted with Waldenström macroglobulinemia (WM). We investigated the characteristics of WM according to mutational status of MYD88/CXCR4, and attempted to determine the lineage commitment among hematopoietic cells by MYD88L265P single-cell sequencing on bone marrow (BM) smear slides. Materials and Methods: CXCR4 mutations (muts) were detected using ultra-deep sequencing using target capture. Mutational burden of MYD88 was assessed using real-time polymerase chain reaction. Single-cell sequencing for MYD88 was performed on lymphocytes, plasmacytoid lymphocytes, plasma cells, and neutrophils using laser microdissection. Results: Among 31 patients, the frequencies of MYD88/CXCR4 muts were as follows: MYD88 wild type (WT) CXCR4WT (6 patients, 19.4%), MYD88L265PCXCR4WT (19 patients, 61.4%), MYD88L265PCXCR4mut (6 patients, 19.4%; 1 frameshift and 5 nonsense muts). Immunoglobulin M levels of MYD88L265CXCR4WT patients were significantly higher than those of MYD88WTCXCR4WT patients (P = .024). Tumor burden in BM was highest in patients with MYD88L265PCXCR4mut (82.0%), followed by MYD88L265PCXCR4WT (52.8%) and MYD88WTCXCR4WT (14.2%) (P < .001). The quantity of MYD88-mutated DNA tended to correlate with tumor burden in BM (correlation coefficient 0.647; P = .009). MYD88L265P was detected in plasma cells, plasmacytoid lymphocytes, and lymphocytes but not neutrophils. Conclusion: The frequency of MYD88/CXCR4 muts in Korean and Caucasian patients with WM was similar, however 5 of the 6 CXCR4 muts were nonsense—a proportion higher than reported frequencies in Caucasian individuals. Ultra-deep sequencing was capable of detecting CXCR4 muts not detectable using Sanger sequencing, suggesting a possible replacement of the B-cell sorting. The frequencies of myeloid differentiation factor 88 (MYD88)/C-X-C chemokine receptor type 4 (CXCR4) mutations and the corresponding clinical characteristics in 31 Korean patients with Waldenström macroglobulinemia were assessed. Ultra-deep sequencing (for CXCR4) and several polymerase chain reaction-based methods (for MYD88) revealed that the frequencies of MYD88/CXCR4 mutations in these Korean patients were similar to reported frequencies for Caucasian individuals. Immunoglobulin M levels and tumor burden were highest in MYD88L265PCXCR4-mutation patients.

Original languageEnglish
Pages (from-to)e496-e505
JournalClinical Lymphoma, Myeloma and Leukemia
Volume19
Issue number8
DOIs
StatePublished - 1 Aug 2019

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Myeloid Differentiation Factor 88
Waldenstrom Macroglobulinemia
CXC Chemokines
High-Throughput Nucleotide Sequencing
Chemokine Receptors
Mutation
Tumor Burden
Lymphocytes
Bone Marrow
Plasma Cells
Immunoglobulin M
Neutrophils
Microdissection
Nonsense Codon
Real-Time Polymerase Chain Reaction

Keywords

  • CXCR4
  • MYD88
  • Single cell analysis
  • Ultra-deep sequencing
  • Waldenström macroglobulinemia

Cite this

Shin, Dong Woo ; Kim, Sung Min ; Kim, Jung Ah ; Park, Hee Sue ; Hwang, Sang Mee ; Im, Kyongok ; Kim, Sungsik ; Kim, Jinhyun ; Kwon, Sunghoon ; Yoon, Sung-Soo ; Lee, Dong Soon. / Characteristics of Waldenström Macroglobulinemia in Korean Patients According to Mutational Status of MYD88 and CXCR4 : Analysis Using Ultra-Deep Sequencing. In: Clinical Lymphoma, Myeloma and Leukemia. 2019 ; Vol. 19, No. 8. pp. e496-e505.
@article{014acae0d83c4f169b46f8270b789dee,
title = "Characteristics of Waldenstr{\"o}m Macroglobulinemia in Korean Patients According to Mutational Status of MYD88 and CXCR4: Analysis Using Ultra-Deep Sequencing",
abstract = "Background: Little is known about the mutational frequency of myeloid differentiation factor 88 (MYD88) and C-X-C chemokine receptor type 4 (CXCR4) and the corresponding characteristics in Asian individuals afflicted with Waldenstr{\"o}m macroglobulinemia (WM). We investigated the characteristics of WM according to mutational status of MYD88/CXCR4, and attempted to determine the lineage commitment among hematopoietic cells by MYD88L265P single-cell sequencing on bone marrow (BM) smear slides. Materials and Methods: CXCR4 mutations (muts) were detected using ultra-deep sequencing using target capture. Mutational burden of MYD88 was assessed using real-time polymerase chain reaction. Single-cell sequencing for MYD88 was performed on lymphocytes, plasmacytoid lymphocytes, plasma cells, and neutrophils using laser microdissection. Results: Among 31 patients, the frequencies of MYD88/CXCR4 muts were as follows: MYD88 wild type (WT) CXCR4WT (6 patients, 19.4{\%}), MYD88L265PCXCR4WT (19 patients, 61.4{\%}), MYD88L265PCXCR4mut (6 patients, 19.4{\%}; 1 frameshift and 5 nonsense muts). Immunoglobulin M levels of MYD88L265CXCR4WT patients were significantly higher than those of MYD88WTCXCR4WT patients (P = .024). Tumor burden in BM was highest in patients with MYD88L265PCXCR4mut (82.0{\%}), followed by MYD88L265PCXCR4WT (52.8{\%}) and MYD88WTCXCR4WT (14.2{\%}) (P < .001). The quantity of MYD88-mutated DNA tended to correlate with tumor burden in BM (correlation coefficient 0.647; P = .009). MYD88L265P was detected in plasma cells, plasmacytoid lymphocytes, and lymphocytes but not neutrophils. Conclusion: The frequency of MYD88/CXCR4 muts in Korean and Caucasian patients with WM was similar, however 5 of the 6 CXCR4 muts were nonsense—a proportion higher than reported frequencies in Caucasian individuals. Ultra-deep sequencing was capable of detecting CXCR4 muts not detectable using Sanger sequencing, suggesting a possible replacement of the B-cell sorting. The frequencies of myeloid differentiation factor 88 (MYD88)/C-X-C chemokine receptor type 4 (CXCR4) mutations and the corresponding clinical characteristics in 31 Korean patients with Waldenstr{\"o}m macroglobulinemia were assessed. Ultra-deep sequencing (for CXCR4) and several polymerase chain reaction-based methods (for MYD88) revealed that the frequencies of MYD88/CXCR4 mutations in these Korean patients were similar to reported frequencies for Caucasian individuals. Immunoglobulin M levels and tumor burden were highest in MYD88L265PCXCR4-mutation patients.",
keywords = "CXCR4, MYD88, Single cell analysis, Ultra-deep sequencing, Waldenstr{\"o}m macroglobulinemia",
author = "Shin, {Dong Woo} and Kim, {Sung Min} and Kim, {Jung Ah} and Park, {Hee Sue} and Hwang, {Sang Mee} and Kyongok Im and Sungsik Kim and Jinhyun Kim and Sunghoon Kwon and Sung-Soo Yoon and Lee, {Dong Soon}",
year = "2019",
month = "8",
day = "1",
doi = "10.1016/j.clml.2019.03.009",
language = "English",
volume = "19",
pages = "e496--e505",
journal = "Clinical Lymphoma, Myeloma and Leukemia",
issn = "2152-2650",
publisher = "Cancer Media Group",
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}

Characteristics of Waldenström Macroglobulinemia in Korean Patients According to Mutational Status of MYD88 and CXCR4 : Analysis Using Ultra-Deep Sequencing. / Shin, Dong Woo; Kim, Sung Min; Kim, Jung Ah; Park, Hee Sue; Hwang, Sang Mee; Im, Kyongok; Kim, Sungsik; Kim, Jinhyun; Kwon, Sunghoon; Yoon, Sung-Soo; Lee, Dong Soon.

In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 19, No. 8, 01.08.2019, p. e496-e505.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Characteristics of Waldenström Macroglobulinemia in Korean Patients According to Mutational Status of MYD88 and CXCR4

T2 - Analysis Using Ultra-Deep Sequencing

AU - Shin, Dong Woo

AU - Kim, Sung Min

AU - Kim, Jung Ah

AU - Park, Hee Sue

AU - Hwang, Sang Mee

AU - Im, Kyongok

AU - Kim, Sungsik

AU - Kim, Jinhyun

AU - Kwon, Sunghoon

AU - Yoon, Sung-Soo

AU - Lee, Dong Soon

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Background: Little is known about the mutational frequency of myeloid differentiation factor 88 (MYD88) and C-X-C chemokine receptor type 4 (CXCR4) and the corresponding characteristics in Asian individuals afflicted with Waldenström macroglobulinemia (WM). We investigated the characteristics of WM according to mutational status of MYD88/CXCR4, and attempted to determine the lineage commitment among hematopoietic cells by MYD88L265P single-cell sequencing on bone marrow (BM) smear slides. Materials and Methods: CXCR4 mutations (muts) were detected using ultra-deep sequencing using target capture. Mutational burden of MYD88 was assessed using real-time polymerase chain reaction. Single-cell sequencing for MYD88 was performed on lymphocytes, plasmacytoid lymphocytes, plasma cells, and neutrophils using laser microdissection. Results: Among 31 patients, the frequencies of MYD88/CXCR4 muts were as follows: MYD88 wild type (WT) CXCR4WT (6 patients, 19.4%), MYD88L265PCXCR4WT (19 patients, 61.4%), MYD88L265PCXCR4mut (6 patients, 19.4%; 1 frameshift and 5 nonsense muts). Immunoglobulin M levels of MYD88L265CXCR4WT patients were significantly higher than those of MYD88WTCXCR4WT patients (P = .024). Tumor burden in BM was highest in patients with MYD88L265PCXCR4mut (82.0%), followed by MYD88L265PCXCR4WT (52.8%) and MYD88WTCXCR4WT (14.2%) (P < .001). The quantity of MYD88-mutated DNA tended to correlate with tumor burden in BM (correlation coefficient 0.647; P = .009). MYD88L265P was detected in plasma cells, plasmacytoid lymphocytes, and lymphocytes but not neutrophils. Conclusion: The frequency of MYD88/CXCR4 muts in Korean and Caucasian patients with WM was similar, however 5 of the 6 CXCR4 muts were nonsense—a proportion higher than reported frequencies in Caucasian individuals. Ultra-deep sequencing was capable of detecting CXCR4 muts not detectable using Sanger sequencing, suggesting a possible replacement of the B-cell sorting. The frequencies of myeloid differentiation factor 88 (MYD88)/C-X-C chemokine receptor type 4 (CXCR4) mutations and the corresponding clinical characteristics in 31 Korean patients with Waldenström macroglobulinemia were assessed. Ultra-deep sequencing (for CXCR4) and several polymerase chain reaction-based methods (for MYD88) revealed that the frequencies of MYD88/CXCR4 mutations in these Korean patients were similar to reported frequencies for Caucasian individuals. Immunoglobulin M levels and tumor burden were highest in MYD88L265PCXCR4-mutation patients.

AB - Background: Little is known about the mutational frequency of myeloid differentiation factor 88 (MYD88) and C-X-C chemokine receptor type 4 (CXCR4) and the corresponding characteristics in Asian individuals afflicted with Waldenström macroglobulinemia (WM). We investigated the characteristics of WM according to mutational status of MYD88/CXCR4, and attempted to determine the lineage commitment among hematopoietic cells by MYD88L265P single-cell sequencing on bone marrow (BM) smear slides. Materials and Methods: CXCR4 mutations (muts) were detected using ultra-deep sequencing using target capture. Mutational burden of MYD88 was assessed using real-time polymerase chain reaction. Single-cell sequencing for MYD88 was performed on lymphocytes, plasmacytoid lymphocytes, plasma cells, and neutrophils using laser microdissection. Results: Among 31 patients, the frequencies of MYD88/CXCR4 muts were as follows: MYD88 wild type (WT) CXCR4WT (6 patients, 19.4%), MYD88L265PCXCR4WT (19 patients, 61.4%), MYD88L265PCXCR4mut (6 patients, 19.4%; 1 frameshift and 5 nonsense muts). Immunoglobulin M levels of MYD88L265CXCR4WT patients were significantly higher than those of MYD88WTCXCR4WT patients (P = .024). Tumor burden in BM was highest in patients with MYD88L265PCXCR4mut (82.0%), followed by MYD88L265PCXCR4WT (52.8%) and MYD88WTCXCR4WT (14.2%) (P < .001). The quantity of MYD88-mutated DNA tended to correlate with tumor burden in BM (correlation coefficient 0.647; P = .009). MYD88L265P was detected in plasma cells, plasmacytoid lymphocytes, and lymphocytes but not neutrophils. Conclusion: The frequency of MYD88/CXCR4 muts in Korean and Caucasian patients with WM was similar, however 5 of the 6 CXCR4 muts were nonsense—a proportion higher than reported frequencies in Caucasian individuals. Ultra-deep sequencing was capable of detecting CXCR4 muts not detectable using Sanger sequencing, suggesting a possible replacement of the B-cell sorting. The frequencies of myeloid differentiation factor 88 (MYD88)/C-X-C chemokine receptor type 4 (CXCR4) mutations and the corresponding clinical characteristics in 31 Korean patients with Waldenström macroglobulinemia were assessed. Ultra-deep sequencing (for CXCR4) and several polymerase chain reaction-based methods (for MYD88) revealed that the frequencies of MYD88/CXCR4 mutations in these Korean patients were similar to reported frequencies for Caucasian individuals. Immunoglobulin M levels and tumor burden were highest in MYD88L265PCXCR4-mutation patients.

KW - CXCR4

KW - MYD88

KW - Single cell analysis

KW - Ultra-deep sequencing

KW - Waldenström macroglobulinemia

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U2 - 10.1016/j.clml.2019.03.009

DO - 10.1016/j.clml.2019.03.009

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JF - Clinical Lymphoma, Myeloma and Leukemia

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