Disease relevance of ABL1

• Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia [1].
• Here we describe the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics [1].
• BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients [2].
• Methylation of the ABL1 promoter in chronic myelogenous leukemia: lack of prognostic significance [3].
• Furthermore, ABL1 methylation was noted in the vast majority of colonies from blast crisis, but not chronic-phase CML [4].
• Suggesting a mechanistic model that features distinct abl-related tyrosine kinase activity levels as essential determinants of centrosomal integrity, this is the first report mechanistically linking p210BCR-ABL oncoprotein activity to centrosomal hypertrophy [5].

Psychiatry related information on ABL1

• Assuming that imatinib could be included in pretransplantation conditioning therapies, we tested whether combinations of imatinib and gamma-irradiation or alkylating agents such as busulfan or treosulfan would display synergistic activity in BCR-ABL-positive chronic myelogenous leukaemia BV173 and EM-3 cell lines [6].
• Both children showed most of the main clinical features of ABLP, including neurological, and ophthalmic symptoms, and mental retardation [7].

High impact information on ABL1

• The BCR-ABL story: bench to bedside and back [8].
• The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib [1].
• The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A, consistent with a multistep pathogenesis of T-ALL [1].
• NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib [1].
• We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines [1].

Chemical compound and disease context of ABL1

• Here we describe the clinical and genetic response to imatinib mesylate treatment of an ETV6/ABL1-positive CML patient diagnosed in blast crisis (BC) [9].
• CONCLUSIONS: The identification of the Philadelphia chromosome and the subsequent discovery that it represents a translocation between the long arms of chromosomes 9 and 22 producing an aberrant tyrosine kinase, known as BCR-ABL1, has catalyzed our understanding and treatment of this hematologic malignancy [10].
• A novel, phosphotyrosine-independent binding interaction between BCR, the Philadelphia chromosome breakpoint cluster region gene product, and the SH2 domain of its translocation partner c-ABL has recently been reported [11].
• BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin [12].
• Human lymphocytes, p53 protein-deficient acute promyelocytic leukemia cell line HL-60, murine pro-B lymphoid cell line BaF3 and its TEL/ABL-transformed clone cells were exposed to idarubicin with and without pre-treatment with amifostine [13].

Biological context of ABL1

• Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs. 5,6) [1].
• We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1 [1].
• Comparing genome-wide gene expression profiles of BCR-ABL1+ pre-B ALL and normal bone marrow pre-B cells by serial analysis of gene expression, many genes involved in pre-B cell receptor signaling are silenced in the leukemia cells [14].
• We recently identified NUP214-ABL1 as a variant ABL1 fusion gene in 6% of T-ALL patients [15].
• Our data suggest that specific methylation of the Ph'-associated ABL1 allele accompanies clonal evolution in CML [4].

Anatomical context of ABL1

• Reversibility of acute B-cell leukaemia induced by BCR-ABL1 [16].
• Clonal eosinophils are a morphologic hallmark of ETV6/ABL1 positive acute myeloid leukemia [17].
• Until d 71 of imatinib mesylate therapy, stable improvements in the clinical and laboratory features were noted, and the frequency of ABL1-rearranged peripheral blood cells decreased from 56% to 11% [9].
• Tyrosine phosphorylation of p95Vav in myeloid cells is regulated by GM-CSF, IL-3 and steel factor and is constitutively increased by p210BCR/ABL [18].
• Expression of ALP1 results in morphological transformation of NIH 3T3 fibroblasts in a cABL-dependent manner [19].

Associations of ABL1 with chemical compounds

• Conversely, leukemia subclones surviving inhibition of BCR-ABL1 by STI571 restore responsiveness to antigen receptor engagement and differentiate into immature B cells expressing immunoglobulin light chains [14].
• To address these issues, we adapted the techniques of methylation-specific PCR and bisulfite-sequencing to study the regulatory regions of ABL1 and other genes with a role in DNA repair or genotoxic stress response [4].
• EPO treatment also resulted in biological effects that were remarkably similar to those of BCR/ABL, including improved viability, altered integrin function, and a weak mitogenic signal [20].
• ABL proteins translated in vitro lack phosphotyrosine, but tyrosine kinase activity is uncovered after immunoprecipitation and removal of lysate components [21].
• AMN107 is a small molecule tyrosine kinase inhibitor developed, in the first instance, as a potent inhibitor of breakpoint cluster region-abelson (BCR-ABL) [22].

Physical interactions of ABL1

• CONCLUSIONS: RIN1 is a directly binding ABL tyrosine kinase activator in cells as well as in a defined-component assay [23].
• Paxillin coprecipitated with p210BCR/ABL and multiple other cellular proteins in myeloid cell lines, suggesting the formation of multimeric complexes [24].
• After BCR/ABL transformation, both the CRKL- and CRK-SH2 domains bound to a new complex of proteins of approximate molecular weight 105-120 kDa [25].
• Molecular cytogenetic analysis confirmed that formation of an ETV6/ABL1 fusion in these patients required at least three chromosomal breaks and showed that each of these translocations is the result of a complex chromosomal rearrangement [26].
• Ku70 coprecipitated with c-ABL and p21 after irradiation [27].

Enzymatic interactions of ABL1

• The second ETV6 allele is not necessarily deleted in acute leukemias with a ETV6/ABL fusion [28].
• We have examined the ability of additional SH2 domains to bind phosphotyrosine-free BCR and compared this with their ability to bind tyrosine-phosphorylated c-ABL 1b [11].
• Kinase experiments demonstrated that in the presence of AAP1, the ability of c-ABL to phosphorylate either glutathione S-transferase-CRK or enolase was inhibited [29].

Regulatory relationships of ABL1

• The shift in ABL transcriptional control to the BCR promoter may play a role in cellular transformation mediated by this rearrangement [30].
• BCR/ABL-induced VEGF expression may contribute to the pathogenesis and increased angiogenesis in CML [12].
• BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-Kinase/AKT pathway [31].
• These data argue that BCR-ABL is directly responsible for the enhanced response to SCF reported in CML progenitor cells [32].
• BCR-ABL fails to inhibit apoptosis in U937 myelomonocytic cells expressing a carboxyl-terminal truncated STAT5 [33].

Other interactions of ABL1

• Loss of p53 impedes the antileukemic response to BCR-ABL inhibition [34].
• Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2 [35].
• Detailed FISH analysis identified a cryptic t(9;12) translocation, and molecular studies confirmed the presence of the ETV6-ABL fusion transcript [36].
• Meg-01 cells express a p185 BCR/ABL oncogene, which may be responsible for the constitutive activation of STAT5 [37].
• Among them, PDGFRbeta, ABL, JAK2, and TRKC are tyrosine kinases (TK) [38].

Analytical, diagnostic and therapeutic context of ABL1

• Using a highly sensitive fluorescence in situ hybridization method with probes for BCR and ABL1 (D-FISH), we studied 37 paired sets of bone marrow and blood specimens, collected within 24 to 96 hours of each other, from 10 patients before and during treatment for chronic myeloid leukemia (CML) [39].
• Patients were analyzed for ABL1-BCR 1b-b3 and/or 1b-b4 transcription by RT-PCR analysis [40].
• Identification of genes differentially regulated by the P210 BCR/ABL1 fusion oncogene using cDNA microarrays [41].
• We performed fluorescent in situ hybridization (FISH) with the recently developed BCR/ABL1 D-FISH probe (QBIOgene, Illkirch, F) on cultured bone marrow and peripheral blood cells of 71 patients with CML, ALL, AML, and myeloproliferative disorder (MPD) [42].
• Recently, small-molecule, combined SRC and ABL1 inhibitors have been developed and entered into clinical trials [10].

References