The 2-phenylaminopyrimidine derivative STI571 has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr/abl fusion protein. The activity of this inhibitor has been demonstrated so far both in vitro with bcr/abl expressing cells derived from leukemic patients, and in vivo on nude mice inoculated with bcr/abl positive cells. Yet, no information is available on whether ...

The major mechanism of action of STI571 is a competitive interference with the ATP-binding site of the Bcr/Abl tyrosine kinase. In the BCR/ABL-positive cell line KBM5, we studied cellular events associated with the in vitro acquisition of resistance to STI571. The emergence of the STI571-resistant phenotype was accompanied by only a marginal increase in the number of copies of the BCR/ABL gene ...

BACKGROUND Current practice guidelines for managing patients with chronic myelogenous leukemia (CML) call for monitoring BCR-ABL transcript concentrations with a quantitative reverse transcription-PCR (qRT-PCR) assay. Because the available laboratory-developed assays lack consensus on the appropriate design, reporting of results, and reference intervals, we developed and evaluated an integrated...

In chronic myeloid leukemia (CML) the classical 9;22 translocation results in a BCR-ABL fusion gene, which encodes chimeric BCR-ABL fusion 210 kD oncoproteins (p210BCR-ABL). The two main p210BCR-ABL fusion variants in CML, b2a2 and b3a2 are examples of well characterized antigens expressed by malignant cells. The possibility of an immunotherapeutic approach involving the fusion part of p210BCR-...

Chronic myeloid leukemia (CML) is characterized by a constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl/T315I is the predominant mutation that causes resistance to Imatinib. In the present study, we synthesized a novel Bcr-Abl inhibitor, HS-543, and investigated its effect on cell survival or apoptosis in CML cells bearing Bcr-Abl/T315I (BaF3/T315I) or wild-type Bcr-Abl (BaF3/WT). HS-5...

Sir, Essential thrombocythemia (ET) is a chronic myeloproliferative disorder (CMPD) characterized by extreme thrombocytosis and megakaryocytic hyperplasia, for which no primary cause can be found.1,2 Strict diagnostic criteria have been proposed by the Polycythemia Vera Study Group (PVSG).1 Karyotypic abnormalities are rare (occurring in approximately 5% of patients) and a specific chromosomal ...

It is well established that the chimeric BCR-ABL gene formed by joining parts of the BCR and ABL genes plays a key role in the pathogenesis of Philadelphia (Ph) chromosome-positive leukemias. We report that simultaneous expression of P210 BCR-ABL and P160 BCR in simian COS-1 cells yielded stable complexes of these two proteins, and induced phosphorylation of P160 BCR on tyrosine residues in viv...

The molecular hallmark of Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) is the expression of 1 of 2 alternate forms of the aberrant BCR-ABL protein—p210BCR-ABL or pl90BCR ABL. The presence of BCR-ABL message provides a target for analyzing the lineage derivation of this disease. We, therefore, studied myeloid and erythroid progenitor involvement in Philadelphia chromosom...

Mena [mammalian Ena (Enabled)]/VASP (vasodilator-stimulated phosphoprotein) proteins are the homologues of Drosophila Ena. In Drosophila, Ena is a substrate of the tyrosine kinase DAbl (Drosophila Abl). However, the link between Abl and the Mena/VASP family is not fully understood in mammals. We previously reported that Abi-1 (Abl interactor 1) promotes phosphorylation of Mena and BCAP (B-cell ...

The p210bcr/abl chimeric protein is considered to be implicated in the pathogenesis of Philadelphia chromosome-positive human leukemias. To investigate its biologic function in vivo, we generated transgenic mice expressing p210bcr/abl driven by the metallothionein enhancer/promoter. Two of six founder mice and the transgenic progeny developed leukemias several months after birth. In the leukemi...