IL-7 receptor is expressed on adult pre-B-cell acute lymphoblastic leukemia and other B-cell derived neoplasms and correlates with expression of proliferation and survival markers

Sasson, Sarah C.; Smith, Sandy; Seddiki, Nabila; Zaunders, John; Bryant, Adam; Koelsch, Kersten K.; Weatherall, Christopher; Munier, C. Mee Ling; McGinley, C; Yeung, Julie; Mulligan, Stephen P.; Moore, John J.; Cooper, David A.; Milliken, Sam; Kelleher, Anthony D.

doi:10.1016/j.cyto.2009.12.001

Cited by 38 publications

(30 citation statements)

References 48 publications

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“…Btk and Blnk were found to be targets of PU.1 and Spi-B in our studies, and they are established as tumor suppressors in human precursor B-ALL (36,42). Expression of the IL-7R has long been known to be a common feature of human childhood or adult B cell leukemia (43,44). Finally, although IL-7 has been previously suggested to be not required for human B cell development, gain-of-function mutations in the human IL7R gene are associated with precursor B-ALL (45,46).…”

Section: Discussionmentioning

confidence: 99%

PU.1 Opposes IL-7–Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase

Christie

Turkistany

et al. 2015

The Journal of Immunology

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Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreΔPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-CreΔPB mice. Enriched pro–B cells from CD19-CreΔPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreΔPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreΔPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreΔPB pro–B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro–B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells.

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Section: Discussionmentioning

confidence: 99%

PU.1 Opposes IL-7–Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase

Christie

Turkistany

et al. 2015

The Journal of Immunology

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“…Dysregulated cell surface receptor expression also is associated with hematopoietic malignancies. To illustrate, IL7R-alpha, IL3R-alpha and c-KIT cell levels are dysregulated in adult ALL [7], AML progenitors [8], and AML1-ET09a [9]. Mutations in HGF receptors also occur that alter signal transduction capacities, and function.…”

Section: Introductionmentioning

confidence: 99%

Dynamic Ligand Modulation of EPO Receptor Pools, and Dysregulation by Polycythemia-Associated EPOR Alleles

et al. 2012

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Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for erythropoiesis; can modulate non-erythroid target tissues; and have been reported to affect the progression of certain cancers. Basic studies of EPOR expression and trafficking, however, have been hindered by low-level EPOR occurrence, and the limited specificity of anti-EPOR antibodies. Consequently, these aspects of EPOR biology are not well defined, nor are actions of polycythemia- associated mutated EPOR alleles. Using novel rabbit monoclonal antibodies to intracellular, PY- activated and extracellular EPOR domains, the following properties of the endogenous hEPOR in erythroid progenitors first are unambiguously defined. 1) High- Mr EPOR forms become obviously expressed only when EPO is limited. 2) EPOR-68K plus -70K species sequentially accumulate, and EPOR-70K comprises an apparent cell surface EPOR population. 3) Brefeldin A, N-glycanase and associated analyses point to EPOR-68K as a core-glycosylated intracellular EPOR pool (of modest size). 4) In contrast to recent reports, EPOR inward trafficking is shown (in UT7epo cells, and primary proerythroblasts) to be sharply ligand-dependent. Beyond this, when C-terminal truncated hEPOR-T mutant alleles as harbored by polycythemia patients are co-expressed with the wild-type EPOR in EPO-dependent erythroid progenitors, several specific events become altered. First, EPOR-T alleles are persistently activated upon EPO- challenge, yet are also subject to apparent turn-over (to low-Mr EPOR products). Furthermore, during exponential cell growth EPOR-T species become both over-represented, and hyper-activated. Interestingly, EPOR-T expression also results in an EPO dose-dependent loss of endogenous wild-type EPOR's (and, therefore, a squelching of EPOR C-terminal- mediated negative feedback effects). New knowledge concerning regulated EPOR expression and trafficking therefore is provided, together with new insight into mechanisms via which mutated EPOR-T polycythemia alleles dysregulate the erythron. Notably, specific new tools also are characterized for studies of EPOR expression, activation, action and metabolism.

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“…Immunotherapies that target cancer while minimizing damage to surrounding lymphocytes and tissues could improve patient outcome. The cytokine interleukin-7 (IL-7) has been identified as a supportive factor for several human lymphocyte malignancies, including Hodgkin's and both B-and T-cell acute and chronic lymphocytic leukemias (Touw et al, 1990;Foss et al, 1995;Long et al, 1995;Barata et al, 2001Barata et al, , 2004Juarez et al, 2007;Scupoli et al, 2007;Cattaruzza et al, 2009;Sasson et al, 2010). Along with Notch ligands and c-kit, IL-7 has a prominent, essential role in early T-and B-cell fate determination.…”

Section: Introductionmentioning

confidence: 99%

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

et al. 2010

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Tumor progression is a multiple step process in which, in addition to oncogenic mutation, other supporting factors can contribute to transformation. The role these factors have in cancer is an open question. Using the El-myc model of B-cell transformation, we evaluated the contribution of the cytokine interleukin-7 (IL-7) in supporting lymphomagenesis. We have previously shown that disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7Ra) in a knock-in mouse model (IL-7Ra 449F ) has minor effects on lymphocyte production, but interferes with the activation of survival effectors. To address the hypothesis that targeted signal ablation would selectively affect lymphocyte transformation, IL-7Ra 449F mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and El-myc mice. We found that the loss of IL-7Ra Y449 signaling prevented Tg IL-7-mediated T-and B-lymphocyte transformation and decreased the development of El-myc-induced B-cell tumors. We showed that the IL-7Ra 449F mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as Elmyc-induced proliferation. This study shows that IL-7Ra Y449 is important for lymphocyte transformation, and that unlike deficiencies in pre-B cell receptor signaling, Myc overexpression cannot compensate for the loss of IL-7Ra signals in early B-cell development.

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IL-7 receptor is expressed on adult pre-B-cell acute lymphoblastic leukemia and other B-cell derived neoplasms and correlates with expression of proliferation and survival markers

Cited by 38 publications

References 48 publications

PU.1 Opposes IL-7–Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase

PU.1 Opposes IL-7–Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase

Dynamic Ligand Modulation of EPO Receptor Pools, and Dysregulation by Polycythemia-Associated EPOR Alleles

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

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