There have been successful examples of targeted therapy improving the outcome of some childhood cancers, such as the addition of an ABL class tyrosine kinase inhibitor to conventional chemotherapy substantially improving the cure rate for patients with BCR-ABL1 positive acute lymphoblastic leukemia.
However, the threshold 70 WT1 copies/104 ABL copies post induction in childhood ALL did not show clinical significance for predicting prognosis (p=0.056).
The incorporation of ABL kinase inhibitors into acute lymphoblastic leukemia management should serve as a model for incorporation of FLT3-targeted agents into clinical care.
The diagnosis of 'Philadelphia like' poor prognosis ALLs is technically challenging but of paramount importance as they are likely to respond to targeted therapy with currently available ABL or JAK inhibitors.
Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase activity.
In addition, generation of Tg for both p210BCR/ABL and Notch1DeltaC developed ALL in a shortened period with Stat5 activation, demonstrating the cooperative oncogenicity of Notch1DeltaC/NICD Delta C with p210BCR/ABL involving Stat5-mediated pathway.
The ABL-BCR fusion protein is a constitutively activated tyrosine kinase thought to play a central role in chronic myeloid leukemia (CML) and Philadelphia (Ph) chromosome acute lymphoid leukemia (ALL).
Significant advances in the treatment of Philadelephia chromosome (Ph)- or BCR-ABL-positive acute lymphocytic leukemia (ALL) have been made since the discovery of the selective ABL tyrosine kinase inhibitors (TKIs).
Within the BCR-ABL-positive subgroups, we identified genes overexpressed (PILRB, STS-1, SPRY1) or underexpressed (TSPAN16, ADAMTSL4) in p185BCR-ABL-positive ALL relative to p210BCR-ABL-positive ALL.
Although the ABL kinase inhibitor imatinib mesylate (Gleevec) provides highly effective treatment for BCR-ABL-positive chronic myelogenous leukemia, it has proven far less efficacious in the treatment of BCR-ABL-positive acute lymphoblastic leukemias (ALLs), many of which sustain deletions of the INK4A-ARF (CDKN2A) tumor suppressor locus.
Detectable by fluorescence in situ hybridization (FISH), these losses of sequence include deletion of the 5' region of the ABL gene and the 3' region of BCR in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), as well as the 5' region of ETO in acute myeloid leukemia (AML) French-American-British type M2 associated with t(8;21), 3'MLL in AML and ALL, and 3' core-binding factor beta (CBFbeta) in AML associated with inv(16).
Deletions from the derivative chromosome 9, der(9), of the translocation, t(9;22)(q34;q11), at the site of the ABL/BCR fusion gene, have been demonstrated by fluorescence in situ hybridisation (FISH), in both Philadelphia chromosome (Ph)-positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL).
A split ABL FISH signal without the involvement of BCR does not represent a t(9;22) translocation, and prognostic implications of this apparent subgroup of ALL cases have not been determined.
In a 25-month follow-up, the transcriptional levels of WT-1, Bcr-Abl, and Abl gene, were quantitatively measured in bone marrow cells from 25 CML or acute lymphoblastic leukemia (ALL) patients with the Ph chromosome.
BCR/ABL fluorescent in situ hybridization study of chronic myeloid leukemia (CML) and Philadelphia(+) (Ph(+)) acute lymphoid leukemia (ALL) indicated that approximately 9% of patients exhibited an atypical hybridization pattern consistent with a submicroscopic deletion of the 5' region of ABL and the 3' region of the BCR genes on the 9q(+) chromosome.
Molecular therapeutic approaches, for example, those directed against the fusion protein BCR-ABL with ABL-tyrosine kinase inhibitor, are on the way to creating a new avenue for the treatment of ALL.
Patients with CML in blast crisis, or with Philadelphia positive acute lymphoblastic leukaemia (ALL), can have a smaller BCR-ABL fusion transcript possessing only the first exon of BCR fused to ABL.
This la-Ph, expressing an acute lymphoblastic leukemia (ALL)-type BCR/ABL transcript, produces a novel P180BCR/ABL fusion protein reflecting deletion of 174 bases (58 amino acids) encoded by the a2 exon of the ABL gene.