|
LEUKEMIA, PHILADELPHIA CHROMOSOME-POSITIVE, RESISTANT TO IMATINIB
|
|
0.700 |
CausalMutation
|
CLINVAR |
|
|
|
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
CLINVAR |
Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.
|
11423618 |
2001 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
CLINVAR |
BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study.
|
11853795 |
2002 |
|
Acute lymphoblastic leukemia with lymphomatous features
|
|
0.700 |
GeneticVariation
|
CLINVAR |
Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation.
|
11861307 |
2002 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
CLINVAR |
High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance.
|
11964322 |
2002 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
CLINVAR |
Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment.
|
12130516 |
2002 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
CLINVAR |
Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy.
|
12399961 |
2002 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
CLINVAR |
Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis.
|
12623848 |
2003 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
CLINVAR |
High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib.
|
14745431 |
2004 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
CLINVAR |
The two major imatinib resistance mutations E255K and T315I enhance the activity of BCR/ABL fusion kinase.
|
15194504 |
2004 |
|
leukemia
|
|
0.100 |
GeneticVariation
|
BEFREE |
The resistance to the tyrosine kinase inhibitor imatinib in BCR/ABL-positive leukemias is mostly associated with mutations in the kinase domain of BCR/ABL, which include the most prevalent mutations E255K and T315I.
|
15194504 |
2004 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
BEFREE |
Interestingly, this substitution is a homologue to the T315I mutation already reported in CML, where it is responsible for acquired resistance to imatinib.
|
15236194 |
2004 |
|
leukemia
|
|
0.100 |
GeneticVariation
|
BEFREE |
More importantly, ON012380 was found to induce apoptosis of all of the known imatinib-resistant mutants at concentrations of <10 nM concentration in vitro and cause regression of leukemias induced by i.v. injection of 32Dcl3 cells expressing the imatinib-resistant BCR-ABL isoform T315I.Daily i.v. dosing for up to 3 weeks with a >100 mg/kg concentration of this agent is well tolerated in rodents, without any hematotoxicity.
|
15677719 |
2005 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
BEFREE |
Assessment and follow-up of the proportion of T315I mutant BCR-ABL transcripts can guide appropriate therapeutic decision making in CML patients.
|
16038734 |
2005 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
BEFREE |
T315I-mutated Bcr-Abl in chronic myeloid leukemia and imatinib: insights from a computational study.
|
16093432 |
2005 |
|
Refractory cancer
|
|
0.010 |
GeneticVariation
|
BEFREE |
However, our study indicates that clinical resistance to nilotinib may be associated with the predominant emergence of T315I.
|
16614241 |
2006 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
BEFREE |
The observation of responses in 3 patients with T315I phenotype-refractory CML or Ph-positive ALL, at doses of MK-0457 associated with no significant extramedullary toxicity, is very encouraging.
|
16990603 |
2007 |
|
B Acute Lymphoblastic Leukemia with t(9;22)(q34.1;q11.2); BCR-ABL1
|
|
0.100 |
GeneticVariation
|
BEFREE |
The observation of responses in 3 patients with T315I phenotype-refractory CML or Ph-positive ALL, at doses of MK-0457 associated with no significant extramedullary toxicity, is very encouraging.
|
16990603 |
2007 |
|
Acute lymphocytic leukemia
|
|
0.050 |
GeneticVariation
|
BEFREE |
Three patients with T315I abl-mutated chronic myeloid leukemia (CML) or Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL) have achieved clinical responses to doses of MK-04547 that are not associated with adverse events.
|
16990603 |
2007 |
|
Precursor Cell Lymphoblastic Leukemia Lymphoma
|
|
0.020 |
GeneticVariation
|
BEFREE |
MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation.
|
16990603 |
2007 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
BEFREE |
We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.
|
17189410 |
2006 |
|
B Acute Lymphoblastic Leukemia with t(9;22)(q34.1;q11.2); BCR-ABL1
|
|
0.100 |
GeneticVariation
|
BEFREE |
We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.
|
17189410 |
2006 |
|
Blast Phase
|
|
0.070 |
GeneticVariation
|
BEFREE |
P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis.
|
17189410 |
2006 |
|
Leukemogenesis
|
|
0.010 |
GeneticVariation
|
BEFREE |
Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190(BCR/ABL)-driven [including p210/p190(BCR/ABL)(T315I)] leukemogenesis without exerting any toxicity.
|
17717597 |
2007 |
|
Myeloid Leukemia, Chronic
|
|
0.800 |
GeneticVariation
|
BEFREE |
Dasatinib and nilotinib are potent tyrosine kinase inhibitors (TKIs) with activity against many imatinib-resistant chronic myeloid leukemia (CML) clones with BCR-ABL kinase domain (KD) mutations, except T315I.
|
17785585 |
2007 |