Aberrant expression of β‐catenin discriminates acute myeloid leukaemia from acute lymphoblastic leukaemia

Serinsöz, Ebru; Neusch, Michael; Büsche, Guntram; Wasielewski, Reinhard von; Kreipe, Hans; Böck, O.

doi:10.1111/j.1365-2141.2004.05049.x

Cited by 42 publications

(34 citation statements)

References 31 publications

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“…Since the overexpression of ␤-catenin results in tumor development in other tissues, we wondered why thymocytes do not respond in a similar manner. The lack of T-cell lymphomas in CAT-Tg mice was consistent with the absence of a documented role for ␤-catenin in human T-cell lymphomas (44,54). In this report, we demonstrate that the expression of oncogenic ␤-catenin in thymocytes at developmental stages that coincide with DNA recombination and a burst of proliferation induces DNA damage, growth arrest, and OIS in vivo.…”

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confidence: 50%

β-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced Senescence in Prelymphomagenic Thymocytes In Vivo

Xu¹,

Yu²,

Subrahmanyam

et al. 2008

Molecular and Cellular Biology

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The expression of ␤-catenin, a potent oncogene, is causally linked to tumorigenesis. Therefore, it was surprising that the transgenic expression of oncogenic ␤-catenin in thymocytes resulted in thymic involution instead of lymphomagenesis. In this report, we demonstrate that this is because the expression of oncogenic ␤-catenin induces DNA damage, growth arrest, oncogene-induced senescence (OIS), and apoptosis of immature thymocytes. In p53-deficient mice, the expression of oncogenic ␤-catenin still results in DNA damage and OIS, but the thymocytes survive and eventually progress to thymic lymphoma. ␤-Catenin-induced thymic lymphomas are distinct from lymphomas that arise in p53 ؊/؊ mice. They are CD4 ؊ CD8؊ , while p53-dependent lymphomas are largely CD4 ؉ CD8 ؉ , and they develop at an earlier age and in the absence of c-Myc expression or Notch1 signaling. Thus, we report that oncogenic ␤-catenin-induced, p53-independent growth arrest and OIS and p53-dependent apoptosis protect developing thymocytes from transformation by oncogenic ␤-catenin.Cells sense and respond to their environment via signaling cascades initiated at the cell surface. These signals are propagated by various mechanisms through the cytoplasm, ultimately resulting in the alteration of gene expression patterns in the nucleus. One such pathway is the canonical Wnt-␤-catenin-T-cell factor (TCF) pathway, which plays a causative role in cancers of the colon (17,23,25,28,61), breast (37, 48), and epidermal (18,26,43) tissues. Accordingly, tissue-specific expression of transgenic ␤-catenin can result in the development of aggressive tumors early in life (13,23,34). Briefly, the secreted extracellular Wnt glycoproteins bind to the Frizzled receptors on the surface of cells. This results in the release of ␤-catenin from a destruction complex, allowing it to accumulate in the cytoplasm. ␤-Catenin then travels to the nucleus, where it binds to the transcription factors TCF/lymphocyte enhancer binding factor to activate the transcription of target genes linked to cellular proliferation and cancer, including c-Myc and cyclin D1 (25, 61). Cancers involving stabilized ␤-catenin often deregulate the tumor suppressor p53, whose function normally impedes tumor formation by inducing growth arrest or apoptosis (24, 28). Thus, p53 appears to be an important impediment to ␤-catenin-induced tumorigenesis; however, the molecular mechanisms remain poorly understood.In the thymus, T-cell development is characterized by the expression of the cell surface markers CD4 and CD8 in the following order: double-negative cells (DN), double-positive cells (DP), and either CD4-or CD8-expressing single-positive (SP) cells that migrate out of the thymus into the periphery. The DN population is further divided into four subpopulations based on the cell surface expression of CD44 and/or CD25 into DN1, DN2, DN3, and DN4. At the DN2 and DN3 stages of development, thymocytes undergo RAG-dependent V(D)J rearrangements to generate the recombined T-cell receptor (TCR) ␤-chain. The generat...

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confidence: 50%

β-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced Senescence in Prelymphomagenic Thymocytes In Vivo

Xu¹,

Yu²,

Subrahmanyam

et al. 2008

Molecular and Cellular Biology

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“…We confirm that b-catenin expression is rapidly lost upon myelomonocytic differentiation. 26,33 Interestingly, our preliminary results show that, depending on the way of maturation, erythroid for example, b-catenin could be reexpressed in CD34À cells (data not shown, and 33 ). We found that in M0-M2 AML patients (no M6 AML was tested), b-catenin expression was correlated with the median percentage of CD34 þ blasts, although this was not the case for M4-M5 AML.…”

Section: Discussionmentioning

confidence: 99%

Expression of β-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis

et al. 2006

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Activation of the Wnt/b-catenin pathway has recently been shown to be crucial to the establishment of leukemic stem cells in chronic myeloid leukemia. We sought to determine whether b-catenin was correlated to clonogenic capacity also in the acute myeloid leukemia (AML) setting. Eighty-two patients were retrospectively evaluated for b-catenin expression by Western blot. b-Catenin was expressed (although at various protein levels) in 61% of patients, and was undetectable in the remaining cases. In our cohort, b-catenin expression was correlated with the clonogenic proliferation of AML-colony forming cells (AML-CFC or CFU-L) in methylcellulose in the presence of 5637-conditioned medium, and more strikingly with self-renewing of leukemic cells, as assessed in vitro by a replating assay. In survival analyses, b-catenin appeared as a new independent prognostic factor predicting poor event-free survival and shortened overall survival (both with Po0.05). Furthermore, variations in b-catenin protein levels were dependent on post-transcriptional mechanisms involving the Wnt/ b-catenin pathway only in leukemic cells. Indeed, b-catenin negative leukemic cells were found to increase b-catenin in response to Wnt3a agonist in contrast to normal counterparts. Altogether, our data pave the way to the evaluation of Wnt pathway inhibition as a new rationale for eradicating the clonogenic pool of AML cells.

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“…In lymphoid neoplasms, the Wnt pathway has been found to play several important roles, such as proliferation, migration, and invasion [16,17]. In acute myeloid leukemia, the β-catenin gene expression has been found to be increased [18].…”

Section: Introductionmentioning

confidence: 99%

The role of β-catenin in chronic myeloproliferative disorders

et al. 2008

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Aberrant expression of β‐catenin discriminates acute myeloid leukaemia from acute lymphoblastic leukaemia

Cited by 42 publications

References 31 publications

β-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced Senescence in Prelymphomagenic Thymocytes In Vivo

β-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced Senescence in Prelymphomagenic Thymocytes In Vivo

Expression of β-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis

The role of β-catenin in chronic myeloproliferative disorders

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