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Query: UMLS:C0023473 (
chronic myeloid leukemia
)
18,916
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Chronic myeloid leukemia
(
CML
) is characterized by a genomic translocation generating a permanently active BCR-ABL oncogene with a complex pattern of atypically tyrosine-phosphorylated proteins that drive the malignant phenotype of
CML
. Recently, the
LIM and SH3 domain protein 1
(
LASP1
) was identified as a component of a six gene signature that is strongly predictive for disease progression and relapse in
CML
patients. However, the underlying mechanisms why
LASP1
expression correlates with dismal outcome remained unresolved. Here, we identified
LASP1
as a novel and overexpressed direct substrate of BCR-ABL in
CML
. We demonstrate that
LASP1
is specifically phosphorylated by BCR-ABL at tyrosine-171 in
CML
patients, which is abolished by tyrosine kinase inhibitor therapy. Further studies revealed that
LASP1
phosphorylation results in an association with CRKL - another specific BCR-ABL substrate and bona fide biomarker for BCR-ABL activity. pLASP1-Y171 binds to non-phosphorylated CRKL at its SH2 domain. Accordingly, the BCR-ABL-mediated pathophysiological hyper-phosphorylation of
LASP1
in
CML
disrupts normal regulation of CRKL and
LASP1
, which likely has implications on downstream BCR-ABL signaling. Collectively, our results suggest that
LASP1
phosphorylation might serve as an additional candidate biomarker for assessment of BCR-ABL activity and provide a first step toward a molecular understanding of
LASP1
function in
CML
.
...
PMID:LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia. 2491 48
Chronic myeloid leukaemia
(
CML
) is a clonal myeloproliferative stem cell disorder characterized by the constitutively active BCR-ABL tyrosine kinase. The
LIM and SH3 domain protein 1
(
LASP1
) has recently been identified as a novel BCR-ABL substrate and is associated with proliferation, migration, tumorigenesis and chemoresistance in several cancers. Furthermore,
LASP1
was shown to bind to the chemokine receptor 4 (CXCR4), thought to be involved in mechanisms of relapse. In order to identify potential
LASP1
-mediated pathways and related factors that may help to further eradicate minimal residual disease (MRD), the effect of
LASP1
on processes involved in progression and maintenance of
CML
was investigated. The present data indicate that not only overexpression of CXCR4, but also knockout of
LASP1
contributes to proliferation, reduced apoptosis and migration as well as increased adhesive potential of K562
CML
cells. Furthermore,
LASP1
depletion in K562
CML
cells leads to decreased cytokine release and reduced NK cell-mediated cytotoxicity towards
CML
cells. Taken together, these results indicate that in
CML
, reduced levels of
LASP1
alone and in combination with high CXCR4 expression may contribute to TKI resistance.
...
PMID:Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance. 3195 90
The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in
chronic myeloid leukemia
(
CML
) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the
LIM and SH3 domain protein 1
(
LASP1
) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of
LASP1
, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of
LASP1
at Y171 abrogated these interactions, suggesting that both
LASP1
phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of
LASP1
in breast cancer and
chronic myeloid leukemia
may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.
...
PMID:Phosphorylation-Dependent Differences in CXCR4-LASP1-AKT1 Interaction between Breast Cancer and Chronic Myeloid Leukemia. 3207 6
