Early generated B1 B cells with restricted BCRs become chronic lymphocytic leukemia with continued c-Myc and low Bmf expression

Hayakawa, Kyoko; Formica, Anthony M.; Brill-Dashoff, Joni; Shinton, Susan A.; Ichikawa, Daiju; Zhou, Yan; Morse, Herbert C.; Hardy, Richard R.

doi:10.1084/jem.20160712

Cited by 53 publications

(90 citation statements)

References 73 publications

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“…In mice, the early generated B-1 derived B1a cells self-renew throughout life (5), and high expression of T-cell leukemia 1 (TCL1) oncogene in B1a cells by transgene (Tg) promoted generation of B-1-derived leukemia/lymphoma in aging, resembling human TCL1 + CLL. This early B-1 B1a cell origin was confirmed by the adoptive transfer of B1a cells present in young mice, including d10 neonatal spleen B1a cells (6). In these B-1 derived B cell leukemia/lymphoma, chromosome loss, syntenic to the 13q14 loss found in human CLL and MCL, also occurred (7).…”

Section: Introductionmentioning

confidence: 78%

“…V H 11/D/J H knock-in mouse line (V H 11t) and transgenic mouse lines, V H 3609μ (ATAμTg), V H 3609/V k 21-5 μκ (ATAμκTg; “3369”), Eμ-hTCL1 Tg, and Thy-1 knockout (Thy-1 KO ) and CD40 −/− mouse lines were all on the C.B17 mouse background, as previously described (6, 19, 24, 40). C.B17 mice were used as wild type.…”

Section: Methodsmentioning

confidence: 99%

“…PBL analyses were performed every 3–4 months for each mouse (6). A predominance of V H 11 + aPtC or ATA B cells in total B cells without increased PBL was defined as MBL.…”

Section: Methodsmentioning

confidence: 99%

“…However, it has been known that cyclin D1 overexpression by transgene in mice is insufficient to detect B cell lymphoma generation, except the case by addition of mitogenic stimulus in aged (15), or together with cMyc transgene or proapoptotic Bcl-2 family protein Bim deficiency (16, 17). Since early generated mouse B-1 B1a cells are known to continue to express moderately up-regulated c-Myc and down-regulated Bmf as another proapoptotic Bcl-2 family protein (6), infrequent B cells with certain restricted BCRs in B1a cells may have the capacity to become MCL-like neoplasia when cyclin D1 is overexpressed.…”

Section: Introductionmentioning

confidence: 99%

“…To assess MCL-like lymphoma generation with potential intestinal involvement, we next analyzed anti-thymocyte/Thy-1 autoreactive (ATA) B cell transgenic (Tg) strains. Generation of mature B1a cells expressing the ATA BCR is also restricted to B-1 development, and increased expression of this ATA BCR by B1a cells led to spontaneous generation of lymphoma in aged mice on the C.B17 (BALB/c.Igh-1 b ) background (6, 24, 25). Studies of these V H 11t and ATA Tg mice, and further analysis of ATA Tg mice co-expressed with Eμ-cyclin D1 transgene, revealed the normal presence of B1a cells in mantle zone areas of the intestine, splenomegaly and mLN hyperplasia generation by ATA B cells in aged mice, and cyclin D1 overexpression by ATA B cells leads to a further diffused pattern of lymphoid neoplasia generation, resembling MCL.…”

Section: Introductionmentioning

confidence: 99%

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Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

Hayakawa

Formica

Nakao

et al. 2018

The Journal of Immunology

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In mice, fetal/neonatal B-1 cell development generates CD5+ B cells (B1a) with autoreactivity. We analyzed B1a cells at the neonatal stage in a VH11/D/JH knock-in mouse line (VH11t) that generates an autoreactive anti-phosphatidylcholine (aPtC) B cell receptors (BCR). Our study revealed that aPtC B1a cells develop in liver, mature in spleen, and distribute in intestine/colon, mesenteric lymph node (mLN) and body cavity, as the outcome of B-1 cell development before B-2 cell development. Throughout life, self-renewing B-1 B1a cells circulate through intestine, mesenteric vessel and blood. The body cavity-deposited B1a cells also re-migrate. In old age, some B1a cells proceed to monoclonal B cell lymphocytosis. When neonatal B-1 B1a cells express an anti-thymocyte/Thy-1 autoreactivity (ATA) BCR transgene in the C.B17 mouse background, ATA B cells increase in PBL and strongly develop lymphomas in aging mice that feature splenomegaly and mLN hyperplasia with heightened expression of CD11b, IL-10, and activated Stat3. At the adult stage, ATA B cells were normally present in the mantle zone area, including in intestine. Furthermore, frequent association with mLN hyperplasia suggests the influence by intestinal microenvironment on lymphoma development. When cyclin D1 was overexpressed by the Eμ-cyclin D1 transgene, ATA B cells progressed to further diffused lymphoma in aged mice, including in various lymph nodes with accumulation of IgMhiIgDloCD5+CD23−CD43+ cells, resembling aggressive human mantle cell lymphoma (MCL). Thus, our findings reveal that early-generated B cells, as an outcome of B-1 cell development, can progress to become lymphocytosis, lymphoma, and MCL-like neoplasia in aged mice.

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Section: Introductionmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

“…PBL analyses were performed every 3–4 months for each mouse (6). A predominance of V H 11 + aPtC or ATA B cells in total B cells without increased PBL was defined as MBL.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

Hayakawa

Formica

Nakao

et al. 2018

The Journal of Immunology

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A new perspective: Exploring future therapeutic strategies for cancer by understanding the dual role of B lymphocytes in tumor immunity

Liu

Sun

Wang

et al. 2018

Intl Journal of Cancer

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Our previous understanding of the role of B lymphocytes in tumor immunity is its antitumor effects. However, further evidence indicates B lymphocytes can also promote tumorigenesis by modulating immune responses. Therefore, the increasingly complex role of B lymphocytes in tumor immunity may become an important factor in tumor immunotherapy. In this review, we describe the development of B cells in tumor microenvironments. We then focus on the most controversial issues of the biological functions of B lymphocytes. Finally, we nominate B cells as therapeutic targets, which should open broad perspectives for the development of their clinical applications.

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Curcumol and FTY720 synergistically induce apoptosis and differentiation in chronic myelomonocytic leukemia via multiple signaling pathways

Zhao

Yang

Chai

et al. 2020

Phytotherapy Research

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Chronic myelomonocytic leukemia (CML) is a myeloid tumor characterized by MDS (myelodysplastic syndrome) and MPN (myeloproliferative neoplasms). Allogeneic hematopoietic stem cell transplantation, chemotherapy, interferon, and targeted therapy are the main treatment methods for CML. Tyrosine kinase inhibitors (TKIs) are also a treatment option, and patients are currently recommended to take these drugs throughout their lives to prevent CML recurrence. Therefore, there is a need to investigate and identify other potential chemotherapy drugs. Currently, research on CML treatment with a single drug has shown little progress. Fingolimod (FTY720), an FDA‐approved drug used to treat relapsing multiple sclerosis, has also shown great potential in the treatment of lymphocytic leukemia. In our study, we find that FTY720 and curcumol have a significant inhibitory effect on K562 cells, K562/ADR cells, and CD34+ cells from CML patients. RNAseq data analysis shows that regulation of apoptosis and differentiation pathways are key pathways in this process. Besides, BCR/ABL–Jak2/STAT3 signaling, PI3K/Akt–Jnk signaling, and activation of BH3‐only genes are involved in CML inhibition. In a K562 xenograft mouse model, therapy with curcumol and FTY720 led to significant inhibition of tumor growth and induction of apoptosis. To summarize, curcumol and FTY720 synergistically inhibit proliferation involved in differentiation and induce apoptosis in CML cells. Therefore, synergistic treatment with two drugs could be the next choice of treatment for CML.

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Early generated B1 B cells with restricted BCRs become chronic lymphocytic leukemia with continued c-Myc and low Bmf expression

Abstract: Hayakawa et al. show that distinctive B-lineage progression from B-1 development allows for generation of B1a cells with restricted BCRs and self-renewal capacity, both contributing to potential for CLL progression.

Cited by 53 publications

References 73 publications

Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

A new perspective: Exploring future therapeutic strategies for cancer by understanding the dual role of B lymphocytes in tumor immunity

Curcumol and FTY720 synergistically induce apoptosis and differentiation in chronic myelomonocytic leukemia via multiple signaling pathways

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