We retrospectively analyzed adults who underwent allogeneic HSCT for CML and Ph + ALL at our institution between 2000 and 2010, and we identified subjects who had detectable BCR-ABL transcripts by polymerase chain reaction (PCR), as well as available RNA for Sanger sequencing of the ABL kinase domain, in both the pre- and post-HSCT settings.
The discovery of targeted ABL tyrosine kinase inhibitors has allowed significant advances in the treatment of de novo Philadelphia chromosome (Ph)-positive ALL.
Chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia are associated with p210BCR/ABL and p185BCR/ABL, respectively.
ABL KD mutations, especially at codons 315 and 253, emerged at the time of disease recurrence in the vast majority of patients who had Ph-positive ALL and received maintenance KI therapy.
Incorporation of ABL-targeted oral tyrosine kinase inhibitors (TKIs) into frontline therapeutic regimens has improved outcomes for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL).
This specific combination of Nutlin-3 and Tanshinone IIA is also effective in preventing the recurrence of refractory leukemia, such as Ph+ ALL with the ABL kinase T315I mutation and AML with the FLT3-ITD mutation.
Imatinib, the ABL kinase inhibitor, is used not only for Philadelphia chromosome-positive (Ph + ) chronic myelogenous leukemia, but also for Ph + acute lymphoblastic leukemia (ALL), although resistance to the drug tends to develop in an early stage of the clinical course.
A dual inhibitor of PI3K and mTOR, PI-103, was more effective than rapamycin at suppressing proliferation of mouse pre-B-ALL and human CD19+CD34+)Ph+ ALL leukemia cells treated with the ABL kinase inhibitor imatinib.
Despite the clinical efficacy achieved with frontline therapies for BCR-ABL-positive disease, such as imatinib and second-generation ABL inhibitors like nilotinib or dasatinib that were originally designed to override insensitivity to imatinib, drug resistance still remains a challenge, especially for patients with advanced-stage chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.
We studied the tyrosine phosphorylated proteins which might be involved in the signaling pathway p185BCR-ABL using a Ph-positive acute lymphoblastic leukemia cell line. p185BCR-ABL but not p145c-abl was constitutively phosphorylated on tyrosine in this cell line. p21ras GTPase-activating protein (GAP) was physically associated with p185BCR-ABL, but not with p145c-abl, and GAP-associated proteins p62/p190 were found to be tyrosine-phosphorylated.
Our study suggests that the origin of both p190BCR-ABL- and p210BCR-ABL-positive ALL is heterogenous with involvement of either a pluripotent precursor or a lymphoid lineage-committed hematopoietic progenitor.
Dasatinib is a small-molecule inhibitor of the tyrosine kinases SRC and ABL that has been approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia.
One patient with lymphoid BC/Ph+ ALL who harbored a T315IABL mutation and was treated with ponatinib was found to have developed a newly acquired V216M TP53 mutation (12% of transcripts) when becoming resistant to ponatinib.
In most cases of CML and some cases of Ph+ ALL the protooncogene ABL from 9q34 is translocated to the breakpoint cluster region (bcr) of the BCR gene at 22q11 to form a chimeric gene encoding a novel 210-kd protein (P210 BCR-ABL) with enhanced tyrosine kinase activity.
The introduction of tyrosine kinase inhibitors (TKIs) targeting the ABL kinase (such as imatinib) has dramatically improved survival of CML and Ph+ ALL patients.
Dasatinib is a second generation ABL kinase inhibitor used in the management of chronic myeloid leukemia or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).