scholarly journals Mechanism of IL-10 Protective Effect in Development of Childhood B Cell Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4075-4075
Author(s):  
Briana Fitch ◽  
Michelle L. Hermiston ◽  
Joseph L. Wiemels ◽  
Scott C. Kogan
Keyword(s):  
Immune Response ◽  
Acute Lymphoblastic Leukemia ◽  
Mouse Model ◽  
B Cell ◽  
Knockout Mice ◽  
Lymphoblastic Leukemia ◽  
Host Immune System ◽  
Increased Risk ◽  
Cell Acute Lymphoblastic Leukemia

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy of childhood. While significant progress has been made in the treatment of B-ALL, the factors that influence the development of B-ALL remain poorly understood. Epidemiological studies have established a role of early childhood infections in altering leukemia risk. The focus of these studies has been on documenting the number and timing of infectious exposures; however, the role of host immune response to infections in B-ALL development is largely unknown. Low birth levels of the immunomodulatory cytokine interleukin 10 (IL-10) are associated with a 25 fold increased risk of developing childhood B-ALL. Mechanistically, IL-10 plays a critical role in controlling the neonatal immune response to infections. Together, these findings suggest that IL-10, an important regulator of host immune responsiveness, protects against childhood B-ALL. To establish whether loss of IL-10 has an impact on leukemogenesis, we crossed Il10 knockout mice to the TEL-AML1 (ETVX6-RUNX1I) Ckdn2anull mouse model of childhood B-ALL. ETV6-RUNX1 t(12;21) is the most frequent chromosomal translocation in childhood B-ALLand one-fourth of these leukemias are observed in combination with loss of the Cdkn2a locus. The leukemia incidence in TEL-AML1 Ckdn2anull mice is 60%, therefore this is a robust and clinically relevant mouse model of childhood B-ALL. We used this model to assess the role of IL-10 in leukemogenesis by following Il10 knockout TEL-AML1 Ckdn2anull mice for the development of disease in comparison with control IL-10 expressing TEL-AML1 Ckdn2anull mice. We found that Il10 knockout accelerated leukemogenesis in the presence of TEL-AML1. The cancer free survival of the IL-10 expressing TEL-AML1 Ckdn2anull mice (n=74) was 227 days, whereas the survival of IL-10 knockout mice (n=40) was reduced to 180 days (p<0.0005). These data support a causal role of low levels of IL-10 in the development of B-ALL and raise the possibility of using an IL-10 receptor agonist for leukemia prevention in children with high risk of B-ALL. Thus, IL-10 loss is a defect in the host immune system that accelerates childhood B-ALL development, potentially through modifying immune responses to infections. Studies to understand the mechanism of how low IL-10 levels interact with infections to influence leukemogenesis are underway. Disclosures No relevant conflicts of interest to declare.

Abstract A44: The role of PHF6 in maintaining pre-B cell commitment in B-cell acute lymphoblastic leukemia

2016 ◽  
Author(s):  
Yadira M. Soto-Feliciano ◽  
Jordan ME Bartlebaugh ◽  
Yunpeng Liu ◽  
Francisco J. Sánchez-Rivera ◽  
Abraham S. Weintraub ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Cell Commitment

Emerging role of immunotherapy in precursor B-cell acute lymphoblastic leukemia

2017 ◽  
Vol 10 (9) ◽  
pp. 783-799 ◽  
Author(s):  
Gautam Kishore Valecha ◽  
Uroosa Ibrahim ◽  
Sassine Ghanem ◽  
Divya Asti ◽  
Jean-Paul Atallah ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

A Critical Role of Blockade of Cell Differentiation in BCR-ABL-Induced B-Cell Acute Lymphoblastic Leukemia (B-ALL): Basis for Superb Therapeutic Effect on B-ALL in Mice by Promotion of Pro-B Leukemic Cell Differentiation and Treatment with Imatinib.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 844-844
Author(s):  
Yiguo Hu ◽  
Linghong Kong ◽  
Kevin Staples ◽  
Kevin Mills ◽  
John G. Monroe ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
B Cell Differentiation ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The BCR-ABL oncogene induces human Philadelphia-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) that advances to acute phase of CML called blast crisis. In this acute phase, CML patients can develop either B-ALL or acute myeloid leukemia. In B-ALL, differentiation of leukemic cells are blocked at pro-/pre-B stage, and the underlying mechanism is unknown. We hypothesize that this blockade of B-cell differentiation may be important for the development of B-ALL induced by BCR-ABL, and if so, promotion of B-leukemic cell differentiation would create a novel therapeutic strategy for B-ALL. To test this hypothesis, we first compared the percentages of IgM+ B-leukemic cells in BALB/c and C57BL/6 (B6) mice with BCR-ABL-induced B-ALL, because we have previously found that B-ALL develops more quickly in BALB/c mice than in B6 mice (Li et al, J. Exp. Med.189:1399–1412, 1999). We expressed BCR-ABL in bone marrow (BM) using retroviral transduction and transplantation in these two different strains of inbred mice to induce B-ALL. There were significantly more peripheral blood B220+ B cells in BALB/c B-ALL mice than those in B6 mice, correlating to faster B-ALL in BALB/c mice than in B6 mice. Among these B220+ cells, IgM+ cells were much less in BALB/c mice than in B6 mice. We also compared rearrangement of the B cell antigen receptor (BCR) heavy chains (m chains) between BALB/c and B6 backgrounds using BCR-ABL-expressing pro-B cell lines isolated from the B-ALL mice. Normal m chains rearrangement was found in B6 leukemic cells, but not in BALB/c leukemic cells. These results indicate that more differentiated B-leukemic cells are associated with less aggressive disease. To further demonstrate the role of blockade of B-cell differentiation in B-ALL development, we induced B-leukemic cell differentiation by co-expression of BCR-ABL and intact immunoregulatory tyrosine activation motifs (ITAM) contained in immunoglobulin (Ig)_/Igß complexes in BM cells of B-ALL mice, comparing to expression of BCR-ABL alone. We treated these mice with imatinib (orally, 100 mg/kg, twice a day). The treated mice with B-ALL induced by co-expression of BCR-ABL and ITAM lived three-week longer than those with B-ALL induced by BCR-ABL only, with some mice in long-term remission. Prolonged survival was associated with 50% increased B220+/IgM+ B-leukemic cells in peripheral blood of the mice. Taken together, our results demonstrate that blockade of B-cell differentiation is critical for the development of B-ALL induced by BCR-ABL, and provide a rationale for combination therapy of B-ALL with imatinib and induction of leukemic cell differentiation.

Hypercalcemia in a Patient with B-Cell Acute Lymphoblastic Leukemia: A Role of Proinflammatory Cytokine

2001 ◽  
Vol 322 (2) ◽  
pp. 109-112 ◽  
Author(s):  
Hirotaka Fukasawa ◽  
Akihiko Kato ◽  
Yoshihide Fujigaki ◽  
Akira Hishida ◽  
Katsuhiko Yonemura ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Proinflammatory Cytokine ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

A critical role of periostin in B-cell acute lymphoblastic leukemia

Leukemia ◽  
2017 ◽  
Vol 31 (8) ◽  
pp. 1835-1837 ◽  
Author(s):  
Z Ma ◽  
X Zhao ◽  
J Huang ◽  
X Jia ◽  
M Deng ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Deletion of genes encoding PU.1 and Spi-B leads to B cell acute lymphoblastic leukemia associated with driver mutations in Janus Kinases

2018 ◽  
Author(s):  
Carolina R. Batista ◽  
Michelle Lim ◽  
Anne-Sophie Laramée ◽  
Faisal Abu-Sardanah ◽  
Li S. Xu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Amino Acid ◽  
Mouse Model ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Driver Mutations ◽  
Janus Kinases ◽  
Cell Acute Lymphoblastic Leukemia

AbstractPrecursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with recurrent mutations that occur in cancer-initiating cells. There is a need to understand how spontaneous driver mutations influence clonal evolution in leukemia. The ETS-transcription factors PU.1 and Spi-B (encoded bySpi1andSpib) execute a critical role in B cell development and serve as complementary tumour suppressors by opposing the proliferative events mediated by IL-7R signaling. Here, we used a mouse model to conditionally deleteSpi1andSpibgenes in developing B cells. These mice developed B-ALL with a median time to euthanasia of 18 weeks. We performed RNA and whole-exome sequencing (WES) on leukemias isolated from Mb1-CreΔPB mice and identified single-nucleotide variants (SNVs) inJak1,Jak3andIkzf3genes, resulting in amino acid changes and in the gain of early stop-codons. JAK3 mutations resulted in amino acid substitutions located in the pseudo-kinase (R653H, V670A) and in the kinase (T844M) domains. Introduction of these mutations into wild-type pro-B cells conferred survival and proliferation advantages. We conclude that mutations in Janus kinases represent secondary drivers of leukemogenesis in the absence of Spi-B and PU.1 transcription factors. This mouse model represents an useful tool to study clonal evolution and tumour heterogeneity in B-ALL.

scholarly journals Myelodysplastic Syndrome with Myelofibrosis Transformed to a Precursor B-Cell Acute Lymphoblastic Leukemia: A Case Report with Review of the Literature

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Ayed A. Algarni ◽  
Mojtaba Akhtari ◽  
Kai Fu
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Review Of The Literature ◽  
Acute Leukemias ◽  
Allogenic Stem Cell Transplantation ◽  
Increased Risk ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Acute Myeloid

Myelodysplastic syndromes (MDS) comprise a group of heterogeneous clonal hematopoietic cell disorders characterized by cytopenias, bone marrow hypercellularity, and increased risk of transformation to acute leukemias. MDS usually transformed to acute myeloid leukemia, and transformation to acute lymphoblastic leukemia (ALL) is rare. Herein, we report a unique patient who presented with MDS with myelofibrosis. Two months after the initial diagnosis, she progressed to a precursor B-cell acute lymphoblastic leukemia. She was treated with induction therapy followed by allogenic stem cell transplantation. She was alive and doing well upon last followup. We have also reviewed the literature and discussed the clinicopathologic features of 36 MDS patients who progressed to ALL reported in the literature.

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