Data di Pubblicazione:
2012
Citazione:
REGENERATION-ASSOCIATED WNT SIGNALING ACTIVATION IN ACUTE MYELOID LEUKEMIA / F. Corlazzoli ; tutore: C. Battaglia ; co-tutore: A. Beghini ; coordinatore: M. Clerici. Universita' degli Studi di Milano, 2012 Feb 02. 24. ciclo, Anno Accademico 2011. [10.13130/corlazzoli-francesca_phd2012-02-02].
Abstract:
Ample evidence exists in mouse models that acute myeloid leukemia (AML)
develops through stepwise acquisition of collaborating genetic and epigenetic
changes in self-renewing leukemia-initiating cells (LICs) that exhibit a committed
myeloid immunophenotype. Recently, critical questions emerged regarding the
characterization of LICs in the CD34+CD38- fraction and the AC133 antigen (a
glycosylation-dependent epitope of CD133) seems to be one of the markers more
appropriate to enrich for the LICs-containing fraction. The requirement of the
Wnt/β-catenin pathway in the pathogenesis of acute myeloid leukemia (AML) has
recently emerged in mouse models. However, its relationship to genetic programs
promoting retention of self-renewing leukemia stem cells (LSCs) remains elusive.
Hence, the need to identify transcriptional programs involved in the maintenance of
a self-renewing state in LSCs. Given the predominant role of transcription factors
(TFs) function in myeloid leukemia and recent progresses in reprogramming
research for a critical role of TFs in the establishment and maintenance of cellular
phenotypes, here we generated a specially designed transcriptional regulators
(TRs) dataset to interrogate expression microarray data obtained from AC133+
cells in AML patients and healthy donors. Our data suggest that the canonical
Wnt/β-catenin signaling is activated in leukemic human long-term reconstituting
AC133+ restricted cells. In a series of molecular and functional studies we found
that leukemic cells AC133+ synthesize and secrete WNT10B, a hematopoietic
stem cells (HSCs) regenerative-associated molecule, and increase the levels of
dephosphorylated β-catenin. Nevertheless, AML AC133+ cells, in zebrafish
embryos, are able to develop ectopic structures by activating organizer markers
that act downstream of the Wnt pathway. In light of the long-known association
between cancer and chronic tissue injury, and because of the higher homeostatic
range of Wnt/β-catenin signaling occurring during regeneration upon an acute
injury, altogether our data provide compelling evidence that regenerationassociated
Wnt signaling exceeds the homeostatic range in human AML and
affects responsive cells whose renewal is promoted by Wnt pathway activity.
Tipologia IRIS:
Tesi di dottorato
Keywords:
AC133 ; WNT10B ; ACUTE MYELOID LEUKEMIA
Elenco autori:
F. Corlazzoli
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