Dataset Information

CD72 regulates the growth of KIT-mutated leukemia cell line Kasumi-1.

ABSTRACT: Gain-of-function mutations in KIT, a member of the receptor type tyrosine kinases, are observed in certain neoplasms, including mast cell tumors (MCTs) and acute myelogenous leukemias (AMLs). A MCT line HMC1.2 harboring the KIT mutation was reported to express CD72, which could suppress the cell proliferation. Here, we examined the ability of CD72 to modify the growth of AMLs harboring gain-of-function KIT mutations. CD72 was expressed on the surface of the AML cell line, Kasumi-1. CD72 ligation by an agonistic antibody BU40 or by a natural ligand CD100, suppressed the proliferation of the Kasumi-1 cells and enhanced cell death, as monitored by caspase-3 cleavage. These responses were associated with the phosphorylation of CD72, the formation of the CD72 - SHP-1 complex and dephosphorylation of src family kinases and JNK. Thus, these results seemed to suggest that CD72 was the therapeutic potential for AML, as is the case of MCTs.

SUBMITTER: Kataoka TR

PROVIDER: S-EPMC3980566 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CD72 regulates the growth of KIT-mutated leukemia cell line Kasumi-1.

Kataoka Tatsuki R TR Kumanogoh Atsushi A Hirata Masahiro M Moriyoshi Koki K Ueshima Chiyuki C Kawahara Masahiro M Tsuruyama Tatsuaki T Haga Hironori H

Scientific reports 20131004

Gain-of-function mutations in KIT, a member of the receptor type tyrosine kinases, are observed in certain neoplasms, including mast cell tumors (MCTs) and acute myelogenous leukemias (AMLs). A MCT line HMC1.2 harboring the KIT mutation was reported to express CD72, which could suppress the cell proliferation. Here, we examined the ability of CD72 to modify the growth of AMLs harboring gain-of-function KIT mutations. CD72 was expressed on the surface of the AML cell line, Kasumi-1. CD72 ligation ...[more]

PMID: 24713856

Similar Datasets

Project description:A new class of non-coding RNAs, known as long non-coding RNAs (lncRNAs), has been recently described. These lncRNAs are implicated to play pivotal roles in various molecular processes, including development and oncogenesis. Gene expression profiling of human B-ALL samples showed differential lncRNA expression in samples with particular cytogenetic abnormalities. One of the most promising lncRNAs identified, designated B-ALL associated long RNA-6 (BALR-6), had the highest expression in patient samples carrying the MLL rearrangement, and is the focus of this study.Here, we performed a series of experiments to define the function of BALR-6, including several novel splice forms that we identified. Functionally, siRNA-mediated knockdown of BALR-6 in human B-ALL cell lines caused reduced cell proliferation and increased cell death. Conversely, overexpression of BALR-6 isoforms in both human and mouse cell lines caused increased proliferation and decreased apoptosis. Overexpression of BALR-6 in murine bone marrow transplantation experiments caused a significant increase in early hematopoietic progenitor populations, suggesting that its dysregulation may cause developmental changes. Notably, the knockdown of BALR-6 resulted in global dysregulation of gene expression. The gene set was enriched for leukemia-associated genes, as well as for the transcriptome regulated by Specificity Protein 1 (SP1). We confirmed changes in the expression of SP1, as well as its known interactor and downstream target CREB1. Luciferase reporter assays demonstrated an enhancement of SP1-mediated transcription in the presence of BALR-6. These data provide a putative mechanism for regulation by BALR-6 in B-ALL.Our findings support a role for the novel lncRNA BALR-6 in promoting cell survival in B-ALL. Furthermore, this lncRNA influences gene expression in B-ALL in a manner consistent with a function in transcriptional regulation. Specifically, our findings suggest that BALR-6 expression regulates the transcriptome downstream of SP1, and that this may underlie the function of BALR-6 in B-ALL.

Project description:In the present study, the ability of the proteasome inhibitor bortezomib (BZ), an oxidative stress-inducing agent, to sensitize acute myeloid leukemia (AML) cells to decitabine (Dacogen®, DAC; a DNA methyltransferase inhibitor), in terms of cell viability and differentiation, was investigated. Kasumi-1 AML (M2) cells were treated with low-dose DAC (10, 50, 100, 200 or 400 n?), with or without BZ (10 nM). Apoptosis and the cell cycle were evaluated after 24 h of treatment through fluorescence-assisted cell sorting (FACS) with Annexin V/propidium iodide and DAPI staining, respectively. The expression levels of CD193, CD11b, CD13, CD14, CD15, CD16 and CD117 surface differentiation markers were evaluated by FACS after 6 days of treatment. The results indicated significant alterations in cell death and cell cycle phases in Kasumi-1 cells following DAC and BZ combination treatment compared to untreated cells and cells with single treatments. Low-dose DAC/BZ combinations significantly enhanced apoptosis and decreased the population of live Kasumi-1 cells, with 100 and 200 nM of DAC and 10 nM BZ appearing to have the most potent synergistic effect according to a combination index. Furthermore, cell cycle profiling revealed that DAC/BZ treatment synergistically led to G0/G1- and G2/M-phase arrest. By contrast, DAC appeared to promote monocytic and granulocytic differentiation of Kasumi-1 cells more effectively alone than in combination with BZ. BZ acted synergistically with low-dose DAC in vitro, leading to enhanced apoptosis and G0/G1- and G2/M-phase arrest in AML cells, hence prohibiting either DNA synthesis or mitosis. Although further in vivo investigation is necessary, these results provide a strong rationale for the implementation of a combination treatment with DAC and bortezomib in AML therapy, followed by DAC alone, which may achieve better clinical responses and possibly partially overcome the frequently encountered DAC resistance of patients with AML.

Project description:BACKGROUND:KIT tyrosine kinase is expressed in mast cells, interstitial cells of Cajal, and hematopoietic cells. Permanently active KIT mutations lead these host cells to tumorigenesis, and to such diseases as mast cell leukemia (MCL), gastrointestinal stromal tumor (GIST), and acute myeloid leukemia (AML). Recently, we reported that in MCL, KIT with mutations (D816V, human; D814Y, mouse) traffics to endolysosomes (EL), where it can then initiate oncogenic signaling. On the other hand, KIT mutants including KITD814Y in GIST accumulate on the Golgi, and from there, activate downstream. KIT mutations, such as N822K, have been found in 30% of core binding factor-AML (CBF-AML) patients. However, how the mutants are tyrosine-phosphorylated and where they activate downstream molecules remain unknown. Moreover, it is unclear whether a KIT mutant other than KITD816V in MCL is able to signal on EL. METHODS:We used leukemia cell lines, such as Kasumi-1 (KITN822K, AML), SKNO-1 (KITN822K, AML), and HMC-1.1 (KITV560G, MCL), to explore how KIT transduces signals in these cells and to examine the signal platform for the mutants using immunofluorescence microscopy and inhibition of intracellular trafficking. RESULTS:In AML cell lines, KITN822K aberrantly localizes to EL. After biosynthesis, KIT traffics to the cell surface via the Golgi and immediately migrates to EL through endocytosis in a manner dependent on its kinase activity. However, results of phosphorylation imaging show that KIT is preferentially activated on the Golgi. Indeed, blockade of KITN822K migration to the Golgi with BFA/M-COPA inhibits the activation of KIT downstream molecules, such as AKT, ERK, and STAT5, indicating that KIT signaling occurs on the Golgi. Moreover, lipid rafts in the Golgi play a role in KIT signaling. Interestingly, KITV560G in HMC-1.1 migrates and activates downstream in a similar manner to KITN822K in Kasumi-1. CONCLUSIONS:In AML, KITN822K mislocalizes to EL. Our findings, however, suggest that the mutant transduces phosphorylation signals on lipid rafts of the Golgi in leukemia cells. Unexpectedly, the KITV560G signal platform in MCL is similar to that of KITN822K in AML. These observations provide new insights into the pathogenic role of KIT mutants as well as that of other mutant molecules.

Dataset Information

CD72 regulates the growth of KIT-mutated leukemia cell line Kasumi-1.

Publications

CD72 regulates the growth of KIT-mutated leukemia cell line Kasumi-1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure