Leukemia stem cells contribute to drug-resistance and relapse in chronic myeloid leukemia and BCR-ABL1 inhibitor monotherapy fails to eliminate them, thereby necessitating alternate therapeutic strategies.
Our data showed that complex BCR-ABL1 signal patterns were associated with leukemic clonal evolution and poorer prognosis in BCR-ABL1 positive leukemia.
BCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph<sup>+</sup>) leukemia is effectively managed with several approved drugs, including ponatinib for BCR-ABL1<sup>T315I</sup>-mutant disease.
Although BCR-ABL tyrosine kinase inhibitors (TKIs) are highly effective in treating CML at chronic phase, a number of patients develop drug resistance due to the inability of TKIs to kill leukemia stem cells (LSCs).
In addition, to clarify whether the epigenetic silencing is affected by BCR-ABL1 inhibition, we assessed the methylation status in the patients at different time intervals following the tyrosine kinase inhibition using imatinib therapy, as the first-line treatment for this type of leukemia.
Cotreatment of neferine and imatinib significantly decreased the expression of BCR-ABL protein and its molecular chaperone heat shock protein 90 (Hsp90) mRNA and protein levels, and further decreased phospho-extracellular regulated protein kinase 1/2 (p-Erk1/2) and myeloid cell leukemia (Mcl-1) expression.
Therefore, the identification and control of downstream molecules/ signaling route of the BCR-ABL1 that are involved in the survival and self-renewal of leukemia stem cells can be an effective treatment strategy to eliminate leukemia stem cells, which supposed to be cured by Musashi2-Numb signaling pathway.
Therapy based on targeted inhibition of BCR-ABL tyrosine kinase has greatly improved the prognosis for patients with Philadelphia chromosome (Ph)-positive leukemia and tyrosine kinase inhibitors (TKI) have become standard therapy.
Digital PCR technology can thus be utilized to predict WT1/ABL1 expression level accurately and should thus be useful for diagnosis or the evaluation of drug efficiency in patients with leukemia.
We presented a series of 12 successful pregnancies in 11 women with BCR-ABL-positive leukemia, whose leukemia was managed with IFN-alpha throughout their pregnancy.
Imatinib is a tyrosine kinase inhibitor for BCR-ABL1 in Philadelphia chromosome-positive (Ph+) leukemia, and development of resistance due to kinase domain mutation is an important issue.
These results provide novel evidence that gadd45b, like gadd45a, functions as a suppressor of BCR-ABL driven leukemia, albeit via a different mechanism.
The prenatal origin of the rearrangement confirms that ETV6-ABL1 is not sufficient to cause overt leukemia, even when combined with the 2 novel fusions.
We will also review the approaches, including optimal donor selection and, conditioning regimens, donor lymphocyte infusion, BCR/ABL-specific CTL, and chimeric antigen receptor-modified T cells, which have been successfully used in the clinic to enhance and preserve anti-leukemia activity, especially GVL effects, without aggravating GVHD or alleviate GVHD.
Collectively, the present results suggest that in the treatment of leukemia, taxodione has potential as a compound with high efficacy to overcome BCR-ABLT315I mutation-mediated resistance in leukemia cells.