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Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

  1. Ashu Kumari1
  2. Cornelia Brendel1
  3. Andreas Hochhaus2,
  4. Andreas Neubauer1, and 
  5. Andreas Burchert1,*
+Author Affiliations
  1. 1 Philipps Universitaet Marburg, Universitaetsklinikum Giessen und Marburg, Klinik fuer Haematologie, Onkologie und Immunologie, Marburg, Germany;
  2. 2 Universitaetsklinikum Jena, Klinik fuer Innere Medizin II, Abt. Haematologie/Onkologie, Jena, Germany
  1. * Corresponding author; email: burchert@staff.uni-marburg.de


BCR-ABL overexpression and stem cell quiescence supposedly contribute to the failure of imatinib mesylate (IM) to eradicate chronic myeloid leukemia (CML). 
However, BCR-ABL expression levels of persisting precursors and the impact of long-term IM therapy on the clearance of CML from primitive and mature bone marrow compartments are unclear. 
Here, we have shown, that the number of BCR-ABL positive precursors decreases significantly in all bone marrow compartments during major molecular remission (MMR). 
More importantly, we were able to demonstrate substantially lower BCR-ABL expression levels in persisting MMR colony forming units (CFU) compared to CML CFU from diagnosis. 
Critically, lower BCR-ABL levels may indeed cause IM insensitivity, since primary murine bone marrow cells engineered to express low amounts of BCR-ABL were substantially less sensitive to IM than BCR-ABL overexpressing cells. 
BCR-ABL overexpression in turn catalyzed the de novo development of point mutations to a greater extend than chemical mutagenesis. 
Thus, MMR is characterized by the persistence of CML clones with low BCR-ABL expression, which may explain their insensitivity to IM and their low propensity to develop IM resistance through kinase point mutations. 
These findings may have implications for future treatment strategies of residual disease in CML.
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