Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
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Target Concepts:
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Query: UMLS:C0023473 (
chronic myeloid leukemia
)
18,916
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Two major transcripts of
lymphoid enhancer factor-1
(
LEF-1
) have been described. The long isoform with b-catenin binding domain functions as a transcriptional enhancer factor. The short isoform derives from an intronic promoter and exhibits dominant negative activity. Recently, alterations of
LEF-1
isoforms distribution have been described in colon cancer. In the current study we employed a quantitative real-time reverse transcription PCR method (TaqMan) to analyze expression of
LEF-1
isoforms in a large cohort of human tumor (n = 304) and tumor-free control samples (n = 56). The highest expression level of
LEF-1
was found in carcinoma samples whereas brain cancer samples expressed little. Expression of
LEF-1
was different in distinct cancer types. For example, the mRNA level of
LEF-1
was lower in testicular tumor samples compared with tumor-free control samples. Besides epithelial cancers, significant
LEF-1
expression was also found in hematopoietic cells. In hematological malignancies, overall
LEF-1
level was higher in lymphocytic leukemias compared with myeloid leukemias and normal hematopoiesis. However, acute myeloid leukemia and acute lymphocytic leukemia showed a significantly increased fraction of the oncogenic
LEF-1
compared with chronic lymphocytic leukemia and
chronic myeloid leukemia
. Taken together, these data suggest that
LEF-1
is abundantly expressed in human tumors and the ratio of the oncogenic and the dominant negative short isoform altered not only in carcinomas but also in leukemia.
...
PMID:Alterations of lymphoid enhancer factor-1 isoform expression in solid tumors and acute leukemias. 1575 19
Recent evidence suggests that a rare population of self-renewing cancer stem cells (CSC) is responsible for cancer progression and therapeutic resistance.
Chronic myeloid leukemia
(
CML
) represents an important paradigm for understanding the genetic and epigenetic events involved in CSC production.
CML
progresses from a chronic phase (CP) in hematopoietic stem cells (HSC) that harbor the BCR-ABL translocation, to blast crisis (BC), characterized by aberrant activation of beta-catenin within granulocyte-macrophage progenitors (GMP). A major barrier to predicting and inhibiting blast crisis transformation has been the identification of mechanisms driving beta-catenin activation. Here we show that BC
CML
myeloid progenitors, in particular GMP, serially transplant leukemia in immunocompromised mice and thus are enriched for leukemia stem cells (LSC). Notably, cDNA sequencing of Wnt/beta-catenin pathway regulatory genes, including adenomatous polyposis coli, GSK3beta, axin 1, beta-catenin,
lymphoid enhancer factor-1
, cyclin D1, and c-myc, revealed a novel in-frame splice deletion of the GSK3beta kinase domain in the GMP of BC samples that was not detectable by sequencing in blasts or normal progenitors. Moreover, BC
CML
progenitors with misspliced GSK3beta have enhanced beta-catenin expression as well as serial engraftment potential while reintroduction of full-length GSK3beta reduces both in vitro replating and leukemic engraftment. We propose that CP
CML
is initiated by BCR-ABL expression in an HSC clone but that progression to BC may include missplicing of GSK3beta in GMP LSC, enabling unphosphorylated beta-catenin to participate in LSC self-renewal. Missplicing of GSK3beta represents a unique mechanism for the emergence of BC
CML
LSC and might provide a novel diagnostic and therapeutic target.
...
PMID:Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation. 1923 56
