Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BCR-ABL1 fusion kinase is frequently associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia but is rare in T-cell acute lymphoblastic leukemia (T-ALL). We recently identified NUP214-ABL1 as a variant ABL1 fusion gene in 6% of T-ALL patients. Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11). Echinoderm microtubule-associated protein-like 1-Abelson 1 (EML1-ABL1) is a constitutively phosphorylated tyrosine kinase that transforms Ba/F3 cells to growth factor-independent growth through activation of survival and proliferation pathways, including extracellular signal-related kinase 1/2 (Erk1/2), signal transducers and activators of transcription 5 (Stat5), and Lyn kinase. Deletion of the coiled-coil domain of EML1 abrogated the transforming properties of the fusion kinase. EML1-ABL1 and breakpoint cluster region (BCR)-ABL1 were equally sensitive to the tyrosine kinase inhibitor imatinib. These data further demonstrate the involvement of ABL1 fusions in the pathogenesis of T-ALL and identify EML1-ABL1 as a novel therapeutic target of imatinib.
 ...
PMID:Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32). 1571

Chromosomal rearrangements involving the ABL1 gene, leading to a BCR-ABL1 fusion gene, have been mainly associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia (ALL). At present, six other genes have been shown to fuse to ABL1. The kinase domain of ABL1 is retained in all chimeric proteins that are also composed of the N-terminal part of the partner protein that often includes a coiled-coil or a helix-loop-helix domain. These latter domains allow oligomerization of the protein that is required for tyrosine kinase activation, cytoskeletal localization, and neoplastic transformation. Fusion genes that have a break in intron 1 or 2 (BCR-ABL1, ETV6-ABL1, ZMIZ1-ABL1, EML1-ABL1, and NUP214-ABL1) have transforming activity, although NUP214-ABL1 requires amplification to be efficient. The NUP214-ABL1 gene is the second most prevalent fusion gene involving ABL1 in malignant hemopathies, with a frequency of 5% in T-cell ALL. Both fusion genes (SFPQ-ABL1 and RCSD1-ABL1) characterized by a break in intron 4 of ABL1 are associated with B-cell ALL, as the chimeric proteins lacked the SH2 domain of ABL1. Screening for ABL1 chimeric genes could be performed in patients with ALL, more particularly in those with T-cell ALL because ABL1 modulates T-cell development and plays a role in cytoskeletal remodeling processes in T cells.
 ...
PMID:ABL1 fusion genes in hematological malignancies: a review. 2143 2

Recent advances in methods of genomic profiling have accelerated our understanding of the biology of oncologic diseases. Accumulating evidence suggests that both histology and molecular signature have prognostic and predictive value. Advances in molecular characterization of solid tumors have made individualized approaches feasible. Personalized chemotherapy and targeted biological therapy based on tumor's individual biologic and molecular profile can optimize efficacy while minimizing toxicity. Molecular testing for activating mutations is routinely performed for several disease subtypes, including non-small cell lung cancer (NSCLC), breast cancer, melanoma and hematological malignancies including CML. For instance, alterations in the epidermal growth factor receptor (EGFR) domain and echinoderm microtubule associated protein-like 4- anaplastic lymphoma kinase (EML4-ALK) translocation are routinely used to guide therapeutic decisions for advanced NSCLC. Several new treatments targeting EGFR family members, novel EML4-ALK inhibitors and MEK inhibitors are currently in clinical development. Availability of targeted therapies makes it easier to integrate early palliative and supportive care in the management of patients with advanced malignancies. This review summarizes recent advances in use of targeted therapy, with a focus on NSCLC and a special emphasis on investigational strategies for individualized treatment, especially in patients with metastatic disease.
...
PMID:Targeted therapy for lung cancer: present and future. 2584 97