In utero and early-life exposure to thirdhand smoke causes profound changes to the immune system

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thirdhand smoke (THS) is the residual tobacco contamination that remains after the smoke clears. We investigated the effects of THS exposure in utero and during early life in a transgenic Cdkn2a knockout mouse model that is vulnerable to the development of leukemia/lymphoma. Female mice, and their offspring, were exposed from the first day of pregnancy to weaning. Plasma cytokines, body weight and hematologic parameters were measured in the offspring. To investigate THS exposure effects on the development of leukemia/lymphoma, bone marrow was collected from control and THS-exposed mice and transplanted into bone-marrow-ablated recipient mice, which were followed for tumor development for one year. We found that in utero and early life THS exposure caused significant changes in plasma cytokine concentrations and in immune cell populations; changes appeared more pronounced in male mice. Spleen and bone marrow B-cell populations were significantly lower in THS-exposed mice. We furthermore observed that THS exposure increased the leukemia/lymphoma-free survival in bone marrow transplantation recipient mice, potentially caused by THS-induced B cell toxicity. A trend towards increased solid tumors in irradiated mice reconstituted with THS exposed bone marrow stimulates the hypothesis that the immunosuppressive effects of in utero and early-life THS exposure might contribute to carcinogenesis by lowering the host defense to other toxic exposures. Our study adds to expanding evidence that THS exposure alters the immune system and that in utero and early life developmental periods represent vulnerable windows of susceptibility for these effects.

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Combination Exposure to Zidovudine plus Sulfamethoxazole-Trimethoprim Diminishes B-Lymphocyte Immune Responses to Pneumocystis murina Infection in Healthy Mice

Clinical and Vaccine Immunology ◽

10.1128/cvi.13.2.193-201.2006 ◽

2006 ◽

Vol 13 (2) ◽

pp. 193-201 ◽

Cited By ~ 4

Author(s):

David J. Feola ◽

Beth A. Garvy

Keyword(s):

Bone Marrow ◽

Immune Response ◽

B Cells ◽

B Cell ◽

B Lymphocyte ◽

Immune Cell ◽

Lavage Fluid ◽

Cell Phenotype ◽

Cell Populations ◽

Control Group

ABSTRACT We have previously shown that zidovudine plus sulfamethoxazole-trimethoprim exposure decreases immune cell populations in the bone marrow of healthy mice by inducing apoptosis. The hypothesis of the current work was that this toxicity would have an adverse impact on the immune response. To determine this, BALB/c mice were treated with zidovudine, sulfamethoxazole-trimethoprim, the combination of both drugs, or vehicle only (control) via oral gavage for 21 days. On day 4 after dosing completion, the mice were infected intratracheally with 1 × 107 Pneumocystis murina organisms. Immune cell populations (in lung digest, bronchoalveolar lavage fluid, tracheobronchial lymph node, and bone marrow samples), the lung Pneumocystis burden, and serum Pneumocystis-specific antibody titers were determined at days 6, 10, and 20 postinfection. While total bone marrow cellularity was recovered by day 6 postinfection in the combination exposure group, B-cell numbers did not recover until 10 days postinfection, primarily due to the persistent depletion of the late pre-B-cell phenotype. The numbers of CD4+ and CD8+ T cells, as well as the numbers of total B cells and activated B cells in tracheobronchial lymph nodes, were decreased at days 10 and 20 as a result of zidovudine plus sulfamethoxazole-trimethoprim exposure compared to the numbers in the control group. No significant differences in lung lavage or lung digest cell populations were observed. There was a trend of a delay in Pneumocystis clearance in the combination treatment group, and Pneumocystis-specific serum immunoglobulin G titers were reduced at day 20 postinfection. Together, these data indicate that the combination of zidovudine and sulfamethoxazole-trimethoprim adversely affects the humoral immune response to Pneumocystis.

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Tumor staging in a Beagle dog with concomitant large B-cell lymphoma and T-cell acute lymphoblastic leukemia

Journal of Veterinary Diagnostic Investigation ◽

10.1177/10406387211011024 ◽

2021 ◽

pp. 104063872110110

Author(s):

Alessandro Ferrari ◽

Marzia Cozzi ◽

Luca Aresu ◽

Valeria Martini

Keyword(s):

Bone Marrow ◽

Lymph Node ◽

T Cell ◽

B Cell ◽

Cell Lymphoma ◽

Tumor Staging ◽

Lymphoblastic Leukemia ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Cell Acute Lymphoblastic Leukemia

An 8-y-old spayed female Beagle dog was presented with peripheral lymphadenomegaly. Lymph node cytology and flow cytometry led to the diagnosis of large B-cell lymphoma (LBCL). We detected minimal percentages of LBCL cells in peripheral blood and bone marrow samples. However, a monomorphic population of neoplastic cells different from those found in the lymph node was found in the bone marrow. T-cell acute lymphoblastic leukemia was suspected based on flow cytometric immunophenotyping. PCR for antigen receptor rearrangement (PARR) revealed clonal rearrangement of both B-cell and T-cell receptors, and the presence of both neoplastic clones in the lymph node, peripheral blood, and bone marrow. The dog was treated with multi-agent chemotherapy but died 46 d following diagnosis. Tumor staging and patient classification are needed to accurately establish a prognosis and select the most appropriate therapeutic protocol.

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Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease

Scientific Reports ◽

10.1038/s41598-021-95039-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Stephanie L. Rellick ◽

Gangqing Hu ◽

Debra Piktel ◽

Karen H. Martin ◽

Werner J. Geldenhuys ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Tumor Cells ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Adherent Cells ◽

Cell Acute Lymphoblastic Leukemia ◽

Minimal Residual

AbstractB-cell acute lymphoblastic leukemia (ALL) is characterized by accumulation of immature hematopoietic cells in the bone marrow, a well-established sanctuary site for leukemic cell survival during treatment. While standard of care treatment results in remission in most patients, a small population of patients will relapse, due to the presence of minimal residual disease (MRD) consisting of dormant, chemotherapy-resistant tumor cells. To interrogate this clinically relevant population of treatment refractory cells, we developed an in vitro cell model in which human ALL cells are grown in co-culture with human derived bone marrow stromal cells or osteoblasts. Within this co-culture, tumor cells are found in suspension, lightly attached to the top of the adherent cells, or buried under the adherent cells in a population that is phase dim (PD) by light microscopy. PD cells are dormant and chemotherapy-resistant, consistent with the population of cells that underlies MRD. In the current study, we characterized the transcriptional signature of PD cells by RNA-Seq, and these data were compared to a published expression data set derived from human MRD B-cell ALL patients. Our comparative analyses revealed that the PD cell population is markedly similar to the MRD expression patterns from the primary cells isolated from patients. We further identified genes and key signaling pathways that are common between the PD tumor cells from co-culture and patient derived MRD cells as potential therapeutic targets for future studies.

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High cortactin expression in B-cell acute lymphoblastic leukemia is associated with increased transendothelial migration and bone marrow relapse

Leukemia ◽

10.1038/s41375-018-0333-4 ◽

2018 ◽

Vol 33 (6) ◽

pp. 1337-1348 ◽

Cited By ~ 3

Author(s):

Martha Velázquez-Avila ◽

Juan Carlos Balandrán ◽

Dalia Ramírez-Ramírez ◽

Mirella Velázquez-Avila ◽

Antonio Sandoval ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Transendothelial Migration ◽

Cell Acute Lymphoblastic Leukemia

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Fluorathene induces programmed cell death and alters growth of immature B cell populations in bone marrow cultures

Toxicology ◽

10.1016/0300-483x(92)90103-l ◽

1992 ◽

Vol 73 (2) ◽

pp. 203-218 ◽

Cited By ~ 9

Author(s):

Fumihiko Hinoshita ◽

Janet A. Hardin ◽

David H. Sherr

Keyword(s):

Bone Marrow ◽

Cell Death ◽

Programmed Cell Death ◽

B Cell ◽

Cell Populations ◽

Bone Marrow Cultures ◽

Marrow Cultures

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TP53INP1 deficiency maintains murine B lymphopoiesis in aged bone marrow through redox-controlled IL-7R/STAT5 signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1809980116 ◽

2018 ◽

Vol 116 (1) ◽

pp. 211-216 ◽

Cited By ~ 2

Author(s):

Bochra Zidi ◽

Christelle Vincent-Fabert ◽

Laurent Pouyet ◽

Marion Seillier ◽

Amelle Vandevelde ◽

...

Keyword(s):

Oxidative Stress ◽

Bone Marrow ◽

B Cells ◽

B Cell ◽

Immune Cell ◽

B Lymphopoiesis ◽

Hematopoietic Stem ◽

Chronic Oxidative Stress ◽

The Impact ◽

Deficient Mice

Bone marrow (BM) produces all blood and immune cells deriving from hematopoietic stem cells (HSCs). The decrease of immune cell production during aging is one of the features of immunosenescence. The impact of redox dysregulation in BM aging is still poorly understood. Here we use TP53INP1-deficient (KO) mice endowed with chronic oxidative stress to assess the influence of aging-associated redox alterations in BM homeostasis. We show that TP53INP1 deletion has no impact on aging-related accumulation of HSCs. In contrast, the aging-related contraction of the lymphoid compartment is mitigated in TP53INP1 KO mice. B cells that accumulate in old KO BM are differentiating cells that can mature into functional B cells. Importantly, this phenotype results from B cell-intrinsic events associated with defective redox control. Finally, we show that oxidative stress in aged TP53INP1-deficient mice maintains STAT5 expression and activation in early B cells, driving high Pax5 expression, which provides a molecular mechanism for maintenance of B cell development upon aging.

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Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2021570118 ◽

2021 ◽

Vol 118 (16) ◽

pp. e2021570118

Author(s):

Thiago Alves da Costa ◽

Jacob N. Peterson ◽

Julie Lang ◽

Jeremy Shulman ◽

Xiayuan Liang ◽

...

Keyword(s):

Bone Marrow ◽

Immune System ◽

B Cells ◽

B Cell ◽

Cell Tolerance ◽

Human Immune System ◽

B Cell Tolerance ◽

Autoreactive B Cells ◽

Cell Clones ◽

Human Immune

Central B cell tolerance, the process restricting the development of many newly generated autoreactive B cells, has been intensely investigated in mouse cells while studies in humans have been hampered by the inability to phenotypically distinguish autoreactive and nonautoreactive immature B cell clones and the difficulty in accessing fresh human bone marrow samples. Using a human immune system mouse model in which all human Igκ+ B cells undergo central tolerance, we discovered that human autoreactive immature B cells exhibit a distinctive phenotype that includes lower activation of ERK and differential expression of CD69, CD81, CXCR4, and other glycoproteins. Human B cells exhibiting these characteristics were observed in fresh human bone marrow tissue biopsy specimens, although differences in marker expression were smaller than in the humanized mouse model. Furthermore, the expression of these markers was slightly altered in autoreactive B cells of humanized mice engrafted with some human immune systems genetically predisposed to autoimmunity. Finally, by treating mice and human immune system mice with a pharmacologic antagonist, we show that signaling by CXCR4 is necessary to prevent both human and mouse autoreactive B cell clones from egressing the bone marrow, indicating that CXCR4 functionally contributes to central B cell tolerance.

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The influence of a dosage regimen of dexamethasone on detection of normal B-cell precursors in the bone marrow of children with BCP-ALL at the end of induction therapy

Pediatric Hematology/Oncology and Immunopathology ◽

10.24287/1726-1708-2020-19-1-53-57 ◽

2020 ◽

Vol 19 (1) ◽

pp. 53-57

Author(s):

E. V. Mikhailova ◽

T. Yu. Verzhbitskaya ◽

J. V. Roumiantseva ◽

O. I. Illarionova ◽

A. A. Semchenkova ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

B Cell ◽

Induction Therapy ◽

Therapy Group ◽

Lymphoblastic Leukemia ◽

Leukemic Cells ◽

Intermittent Therapy ◽

Continuous Therapy ◽

B Cell Precursors

Minimal residual disease (MRD) monitoring by flow cytometry at the end of induction therapy is one of the key ways of a prognosis assessment in patients with acute lymphoblastic leukemia (ALL). In B-cell precursor ALL (BCP–ALL), this method of MRD detection is complicated due to the immunophenotypic similarity between leukemic cells and normal B-cell precursors (BCPs). A decrease in intensity of induction therapy can lead to a more frequent appearance of normal BCPs in the bone marrow, which significantly complicates the MRD monitoring. Aim: to assess the incidence of normal BCPs in bone marrow on the 36th day of induction therapy with two different regimens of glucocorticoid (GC) administration according to ALL-MB 2015 protocol. This study was approved by the Independent Ethical Committee and the Academic Council of Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology Ministry of Healthcare of Russian Federation. The study included 220 patients with BCP-ALL who were randomized to two types of GC-based induction therapy: a continuous administration of dexamethasone (n = 139) and an intermittent regimen with a 1-week dexamethasone therapy stop (n = 81). On the 36th day of induction therapy, MRD and normal BCPs were quantified in bone marrow samples by flow cytometry. On the 36th day of treatment, 43.2% of BCP(+) samples were established in the intermittent-therapy group, and 27.3% in the continuous-therapy group (p = 0.016). Comparison of the BCP level in BCP(+) samples revealed the more equitable distribution of BCPs at different developmental stages in the intermittent-therapy group, meanwhile mainly the immature BCPs in a quantity of less than 0.01% were found in the continuous-therapy group. Reduced-intensity induction therapy for patients with BCP-ALL leads to a noticeable increase of normal BCPs in bone marrow at the end of this treatment stage. A higher rate of BCP(+) bone marrow samples hinder the MRD detection due to the immunophenotypic similarity of BCPs and leukemic cells.

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Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v83.7.1731.1731 ◽

1994 ◽

Vol 83 (7) ◽

pp. 1731-1737 ◽

Cited By ~ 54

Author(s):

A Manabe ◽

E Coustan-Smith ◽

M Kumagai ◽

FG Behm ◽

SC Raimondi ◽

...

Keyword(s):

Bone Marrow ◽

Cell Death ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Programmed Cell Death ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Fatal Outcome ◽

Interleukin 4 ◽

B Lineage

Abstract We investigated the effects of interleukin-4 (IL-4) on the survival of leukemic and normal B-cell progenitors cultured on bone marrow stroma. IL-4 (at 100 U/mL) was cytotoxic in 16 of 21 cases of B-lineage acute lymphoblastic leukemia, causing reductions in CD19+ cell numbers that ranged from 50% to greater than 99% (median 83.5%) of those in parallel cultures not exposed to the cytokine. All nine cases with the t(9;22)(q34;q11) or the t(4;11)(q21;q23), chromosomal features that are often associated with multidrug resistance and a fatal outcome, were susceptible to IL-4 toxicity. IL-4 cytotoxicity resulted from induction of programmed cell death (apoptosis); there was no evidence of cell killing mediated by T, natural killer, or stromal cells. IL-4 cytotoxicity extended to a proportion of normal B-cell progenitors. After 7 days of culture with IL-4 at 100 U/mL, fewer CD19+, CD34+ normal lymphoblasts (the most immature subset) survived: in five experiments the mean (+/- SEM) reduction in cell recoveries caused by IL-4 was 60.0% +/- 6.0%. By contrast, reductions in recovery of more differentiated bone marrow B cells (CD19+, CD34-, surface Ig+) were low (6.6% +/- 2.2%; P < .001 by t-test). Our findings indicate that IL-4 is cytotoxic for human B-cell precursors and support clinical testing of IL-4 in cases of high-risk lymphoblastic leukemia resistant to conventional therapy.

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