Constitutively active bcr abl tyrosine kinase leukemia myelogenous chronic bcr abl positive. Medical search. Frequent questions

Huang, HM & Liu, JC 2009, ' c-Jun blocks cell differentiation but not growth inhibition or apoptosis of chronic myelogenous leukemia cells induced by STI571 and by histone deacetylase inhibitors ', Journal of Cellular Physiology , vol. 218, no. 3, pp. 568-574. (tmu.edu.tw)
Different inhibitors have been designed to target different kinases: Inhibition of BCR/ABl constitutes the basis of the functioning of drugs like imatinib Inhibition of FLT3 is carried out by drugs like lestaurtinib Inhibition of JAK2 is carried out by the drug CYT387, which was successful in preclinical trials and is currently undergoing clinical trials. (wikipedia.org)
The development of targeted therapies has also been followed by resistance, reminiscent of an evolutionary arms race, as exemplified by imatinib and other BCR-ABL inhibitors for the treatment of chronic myelogenous leukaemia. (nature.com)
Like all tyrosine-kinase inhibitors, imatinib works by preventing a tyrosine kinase enzyme, in this case BCR-Abl, from phosphorylating subsequent proteins and initiating the signaling cascade necessary for cancer development, thus preventing the growth of cancer cells and leading to their death by apoptosis. (keralapharmacist.com)
BCR-Abl is the target of selective inhibitors, such as imatinib (Gleevec), used in the treatment of CML. (umbc.edu)
Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. (ashpublications.org)
In Section II, Dr. James Griffin reviews the mechanisms that lead to activation of tyrosine kinases by mutations in AML, the consequences of that activation for the cell, and the opportunities for targeted therapy and discusses some examples of developing novel drugs (tyrosine kinase inhibitors) and their effectiveness in AML (FLT3). (ashpublications.org)
Chronic Myeloid Leukemia (CML) is a stem cell disease sustained by a rare population of quiescent cells which are to some extent resistant to tyrosine kinase inhibitors (TKIs). (oncotarget.com)

Attempts at treatment for cancer cells with constitutively phosphorylated STAT5 have included both indirect and direct inhibition of STAT5 activity. (wikipedia.org)
Indirect inhibition targets kinases associated with STAT5, or targets proteases that carry out terminal truncation of proteins. (wikipedia.org)
Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions. (keralapharmacist.com)

In response to DNA damage or oxidative stress, Abl is transported to the nucleus where it induces apoptosis. (umbc.edu)

The Tel-ARG fusion protein, resulting from reciprocal translocation between chromosomes 1 and 12, is associated with acute myeloid leukemia (AML). (umbc.edu)
To identify regulators of primitive chronic myeloid leukemia (CML) cells, we performed a high-content cytokine screen using primary CD34 + CD38 low chronic phase CML cells. (haematologica.org)
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by an acquired 9;22-chromosomal translocation in a hematopoietic stem cell (HSC) resulting in the expression of the BCR-ABL1 fusion protein. (haematologica.org)
7 In CML and acute myeloid leukemia (AML), we and others have shown that IL-1 is a positive regulator of LSC, and blocking IL-1 signaling inhibits the LSC. (haematologica.org)
Acute myeloid leukemia (AML) patients with a high allelic burden of an internal tandem duplication ( ITD )-mutated FMS - like Tyrosine Kinase - 3 ( FLT3 ) have a dismal outcome. (biomedcentral.com)
Acute myeloid leukemia (AML) is mainly a fatal disease. (biomedcentral.com)
Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. (ashpublications.org)
FLT3 is frequently mutated in patients with acute myeloid leukemia (AML), which correlates with poor prognosis and decreased patient survival. (ashpublications.org)
The therapeutic approach to the patient with acute myeloid leukemia (AML) currently evolves toward new frontiers. (ashpublications.org)
The term acute myeloid leukemia (AML) collectively refers to a mixture of distinct diseases that differ with regard to their pathogenetic evolution, genetic abnormalities, clinical features, response to therapy, and prognosis. (ashpublications.org)
Here, we comprehensively investigated for the first time TERRA expression in primary human hematopoietic cells from an exploratory cohort of patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), telomere-biology disorder (TBD), and healthy subjects. (bvsalud.org)
Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy that relies on highly heterogeneous cytogenetic alterations. (mdpi.com)
This mechanism also applies to hematopoietic cells transformed by other HOX genes, including CDX2, which is highly expressed in a majority of acute myeloid leukemias, thus providing a molecular approach based on GSK-3 inhibitory strategies to target HOX-associated transcription in a broad spectrum of leukemias. (stanford.edu)
In addition, the BCR-ABL fusion gene product, a constitutively activated tyrosine kinase which is crucial for the development of chronic myeloid leukemia (CML), is highly sensitive to bosutinib. (mdm2-receptor.com)

The Bcr-Abl protein induces the upregulation of proto-oncogene c-Jun, which is involved in Bcr-Abl transforming activity in Bcr-Abl positive cells. (tmu.edu.tw)
The dimerized STAT5 represents the active form of the protein, which is ready for translocation into the nucleus. (wikipedia.org)
STAT5 has been found to be constitutively phosphorylated in cancer cells, implying that the protein is always present in its active form. (wikipedia.org)
In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. (keralapharmacist.com)
The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. (keralapharmacist.com)
Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively. (keralapharmacist.com)
Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. (keralapharmacist.com)
Catalytic domain of the Protein Tyrosine Kinase, Abelson kinase. (umbc.edu)
The PTKc family is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, and phosphoinositide 3-kinase (PI3K). (umbc.edu)
PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. (umbc.edu)
The resulting BCR-Abl fusion protein is constitutively active and associates into tetramers, resulting in a hyperactive kinase sending a continuous signal. (umbc.edu)
1 The BCR-ABL1 fusion protein is a constitutively active tyrosine kinase and triggers a cascade of aberrant downstream signaling pathways leading to clonal outgrowth of CML cells and subsequent disease manifestation. (haematologica.org)
This fusion gene encodes for the FIP1L1-PDGFR alpha protein, the constitutively activated tyrosine kinase activity that induces eosinophilia. (medscape.com)
Docking protein 1 is constitutively tyrosine phosphorylated in hematopoietic progenitors isolated from chronic myelogenous leukemia (CML) patients in the chronic phase. (novusbio.com)
It may be a critical substrate for p210(bcr/abl), a chimeric protein whose presence is associated with CML. (novusbio.com)
Inactivation of the PI3-kinase pathway, but not of Ras-mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. (ashpublications.org)
Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization. (cancerbiomed.org)
We demonstrate here that GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation. (stanford.edu)
The tyrosine kinase Src is a member of a family of related kinases known as the Src family kinases (SFKs) that share a common structural organization and function as key regulators of signal transduction pathways triggered by a wide variety of surface receptors, including receptor tyrosine kinases, integrins, G-protein-coupled receptors, and antigen receptors (Thomas and Brugge 1997). (mdm2-receptor.com)

Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor). (keralapharmacist.com)

Abl is normally inactive and requires phosphorylation and myristoylation for activation. (umbc.edu)
Our results showed that CP-CML CD34+ progenitors were characterized by significant lower phosphorylation of proteins involved in the regulation of growth and cell survival, such as tyrosine kinases of the Src family and members of STAT family, and by a significant higher phosphorylation of p53 (Ser15), compared to normal CD34+ cells from healthy donors. (oncotarget.com)
Interestingly, distinctly lower concentrations of bosutinib are required to ablate BCR-ABL phosphorylation when compared to the first-generation tyrosine kinase inhibitor imatinib (IM). (mdm2-receptor.com)

This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation. (keralapharmacist.com)
Remarkably, bosutinib has been found to be capable of overcoming the majority of IM-resistant BCR-ABL mutations. (mdm2-receptor.com)

Imatinib, marketed by Novartis as Gleevec (U.S.) or Glivec (Europe/Australia/Latin America), and sometimes referred to by its investigational name STI-571, is a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). (keralapharmacist.com)
Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form of targeted therapy-only cancer cells are killed through the drug's action. (keralapharmacist.com)
Imatinib is used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. (keralapharmacist.com)
One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-Kit.However, since imatinib binds to tyrosine kinases when they are in the inactive configuration and the D816V mutant of c-Kit is constitutively active, imatinib does not inhibit the kinase activity of the D816V mutant of c-Kit. (keralapharmacist.com)
Imatinib is a 2-phenyl amino pyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. (keralapharmacist.com)
As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity. (keralapharmacist.com)
Imatinib is quite selective for bcr-abl - it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. (keralapharmacist.com)
Bosutinib has the potency to induce deep and fast responses in second- and third-/fourth-line treatment, and as a consequence, the drug has recently been licensed for patients previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. (mdm2-receptor.com)

FLT3 ITD constitutively activates a signaling network, including the RAS- and STAT-signaling pathways. (biomedcentral.com)
BCR-ABL oncogene activates multiple cross-talking signal transduction pathways (STP), such as RAS/MEK/ERK, PI3K/Akt, Wnt and STAT5, contributing to abnormal proliferation of clonal cells. (oncotarget.com)

Approximately 95% of all CML patients harbor the gene fusion, BCR-ABL, which is formed via a double stranded break (DSB) within both the Abelson oncogene 1 (ABL) on chromosome 9q, which codes for a non-receptor tyrosine kinase (ABL), and the breakpoint cluster region gene (BCR) on chromosome 22q. (ubc.ca)
Abl2, also known as ARG (Abelson-related gene), is thought to play a cooperative role with Abl in the proper development of the nervous system. (umbc.edu)

FLT3 (FMS-like tyrosine kinase 3) is a type III receptor tyrosine kinase (RTK) closely related to the platelet-derived growth factor (PDGF) receptor and c-Kit with important functions in the regulation of early hematopoietic cells. (ashpublications.org)

BCR-ABL encodes a constitutively active tyrosine kinase BCR-ABL responsible for the uncontrolled proliferation associated with chronic myelogenous leukemia. (ubc.ca)

We generated a triple transgenic mouse model, in which tamoxifen-inducible Cre-recombinase targets expression of a constitutively nuclear transcription factor NFATC1 to FLT3 ITD positive HSC. (biomedcentral.com)
2006). In addition, more than 45 other tyrosine and serine/threonine kinases have been identified as potential targets of bosutinib. (mdm2-receptor.com)

Chromosomal translocations can cause cancer, often through the formation of fusion genes that code for an unnatural tyrosine kinase that promotes constitutive activation of a signaling pathway controlling cell proliferation and differentiation. (ubc.ca)
In the cytoplasm, Abl plays a role in cell proliferation and survival. (umbc.edu)
Acute leukemias induced by MLL chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on GSK-3 kinase activity for sustained proliferation. (stanford.edu)
From this perspective, the aim of this study was to analyze the expression and activation profile of STP involved in the mechanisms of cell proliferation/quiescence and survival of the progenitor CD34+ cells from chronic phase (CP) CML. (oncotarget.com)
Bosutinib is a potent inhibitor of CML cell proliferation in vitro and has demonstrated promising activity in CML patients resistant or intolerant to IM as well as in newly diagnosed patients with chronic phase CML (CML-CP). (mdm2-receptor.com)

3 Myelofibrosis (MF) refers to the Philadelphia chromosome ( BCR-ABL1 )-negative myeloproliferative neoplasm (MPN) originating at the level of the multipotent hematopoietic stem cell. (haematologica.org)
In summary, we identify myostatin propeptide as a novel positive regulator of primitive CML cells and corresponding normal hematopoietic cells. (haematologica.org)
Our research focuses on developmental pathways that regulate hematopoietic cell growth and differentiation and are disrupted in the course of neoplastic transformation, particularly in leukemias and lymphomas. (stanford.edu)

For example, the diagnostic hallmark of chronic myelogenous leukemia (CML) is an oncogene fusion formed from a reciprocal translocation (t(9;22)(q34.1;q11.2)) between chromosomes 9 and 22 that results in an altered chromosome 22q known as the Philadelphia chromosome. (ubc.ca)

The constitutively active Bcr-Abl tyrosine kinase plays a crucial role in chronic myelogenous leukemia (CML) pathogenesis. (tmu.edu.tw)
In addition to these basic issues concerning leukemia pathogenesis, we are devising new diagnostic procedures for detecting and monitoring leukemia patients based on molecular genetic abnormalities in the malignant cells. (stanford.edu)

FLT3 ITD /NFATC1-AML is re-transplantable in secondary recipients and shows primary resistance to the FLT3 ITD -kinase inhibitor quizartinib. (biomedcentral.com)
Bosutinib (SKI-606) is a 4-anilino-3-quinoline carbonitrile, which acts as a dual inhibitor of Src and ABL kinases. (mdm2-receptor.com)
Bosutinib (SKI-606), 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3- (4-methyl-1-piperazinyl) propoxy]-3-quinolinecarbonitrile monohydrate, is a competitive inhibitor of both Src and ABL tyrosine kinases. (mdm2-receptor.com)
It was originally synthesized as an inhibitor of the Src kinase family. (mdm2-receptor.com)
Bosutinib is a potent dual inhibitor of the Src and ABL tyrosine kinases (Puttini et al. (mdm2-receptor.com)

It is phosphorylated by ceramide kinase (CK) to form ceramide-1-phosphate or it can be glycosylated by glucosylceramide synthase to form glycosphingolipids (cerebrosides, globosides, gangliosides). (frontiersin.org)
Sphingosine may be phosphorylated by sphingosine kinase 1/2 (SPHK1/SPHK2) to form sphingosine-1-phosphate (S1P), which has a prosurvival role and is critical for immunomodulation ( 1 , 4 , 5 ) ( Figure 2 ). (frontiersin.org)

Aberrant STAT5 activity has been shown to be closely connected to a wide range of human cancers, and silencing this aberrant activity is an area of active research in medicinal chemistry. (wikipedia.org)
In chronic myelogenous leukemia (CML) patients, an aberrant translocation results in the replacement of the first exon of Abl with the BCR (breakpoint cluster region) gene. (umbc.edu)
Aberrant NFAT signaling is causally involved in the development of chronic lymphocytic leukemia, non-Hodgkin lymphoma, pancreatic cancer, and several other malignancies. (biomedcentral.com)

Methotrexate, a folic acid analog/antimetabolite, can be curative for women with choriocarcinoma and is also useful for non-Hodgkin lymphomas and acute lymphocytic leukemias (ALLs) in children. (medquizzes.net)

Some tumor cells, however, have a dependence on bcr-abl. (keralapharmacist.com)

It occupies the TK active site, leading to a decrease in activity. (keralapharmacist.com)

Moreover, several evidence suggests that chronic inflammation and alterations in stromal and immune cells may contribute to MPN's pathophysiology. (bvsalud.org)

In Section III, Dr. Martin Tallman describes the evaluation and management of patients with acute promyelocytic leukemia, a notable example of therapeutic progress in a molecularly defined entity of leukemia. (ashpublications.org)

The identification of these translocation events and/or associated fusion genes in clinical samples is critical to ensure the appropriate treatment for patients where the drug and related course of therapy target an activated fusion kinase. (ubc.ca)
Subsequent clinical trials have confirmed the utility of this drug in ERα-positive breast cancer patients and tamoxifen has now been given to millions of women and has saved countless lives. (biomedcentral.com)
The TEL gene is a frequent fusion partner of other tyr kinase oncogenes, including Tel/Abl, Tel/PDGFRbeta, and Tel/Jak2, found in patients with leukemia and myeloproliferative disorders. (umbc.edu)
The literature now favors the view that cases of idiopathic hypereosinophilic syndrome with FIP1L1 indeed represent chronic eosinophilic leukemia, because these patients have a molecular genetic abnormality, specifically an FIP1L1-PDGFRA fusion gene. (medscape.com)

The second provides for the highly sensitive detection of DSBs in the anaplastic lymphoma kinase (ALK) gene that result in a non-reciprocal (inversion) translocation (inv(2)(p21;p23)) associated with an ALK-positive non-small cell lung cancer (NSCLC). (ubc.ca)

In such cases, a diagnosis of chronic eosinophilic leukemia is made in retrospect when acute transformation provides indirect evidence that the condition was likely to have been a clonal, neoplastic, MPD from the beginning. (medscape.com)

In the activation pathway illustrated to the left, the ligand involved is a cytokine and the specific kinase taking part in activation is JAK. (wikipedia.org)

In the pediatric population, B-acute lymphoblastic leukemia (B-ALL) is the most prevalent childhood hematological malignancy, as well as the leading cause of childhood cancer-related mortality. (biomedcentral.com)

Abl (or c-Abl) is a ubiquitously-expressed cytoplasmic (or nonreceptor) tyr kinase that contains SH3, SH2, and tyr kinase domains in its N-terminal region, as well as nuclear localization motifs, a putative DNA-binding domain, and F- and G-actin binding domains in its C-terminal tail. (umbc.edu)

Anatomy24

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