Keywords
Leukemic Stem Cell
CD26
Deep Molecular Response
How to Cite
Abstract
Chronic Myeloid Leukemia (CML) is characterized by the reciprocal translocation t(9;22)(q34;q21) resulting in the BCR-ABL1 fusion gene encoding the P210 oncoprotein with a constitutive tyrosine kinase (TK) activity. It is known that patients with at least two years in deep and sustained molecular response could stop TK inhibitor (TKI) treatment. However, half of them show molecular recurrence, probably due to the persistence of transcriptionally quiescent leukemic stem cells (LSC). Recent studies show that the expression of the enzyme dipeptidylpeptidase IV (CD26) is mainly restricted to the CD45+/CD34+/CD38- fraction in CML LSC, and it is not found in other myeloid/lymphoid LSC or in normal bone marrow. For this reason, CD26 is considered a novel
specific biomarker in CML.
The aim of this study was to detect the CD26+ LSC in CML patients with different molecular responses (MR) and to assess if these cells remain even in deep molecular response (DMR).
We have evaluated 193 CML patients (107 males and 86 females) for detection of LSC by flow cytometry using the panel: CD45, CD34, CD38, CD26, CD117, CD123, CD3 and HLA-DR and the BCR-ABL1 quantification by qRT-PCR (Taqman method). Both studies were carried out simultaneously on the same sample, during the follow up at different time points under TKI treatment (Imatinib, Nilotinib, Dasatinib).
Patients with ≥ 3 BCR-ABL1 log reduction had a significantly lower percentage of cases with CD26+ LSC compared with those who had < 3 log reduction (p<0.0003, OR: 3.4, 95% CI: 1,7 - 6,8). Out of the 76 patients with DMR (33 in MR4.0, 38 in MR4.5 and 5 in MR5.0) only 12/76 (16%) showed persistence of CD26+ LSC. Furthermore, the presence of CD26+ LSC decreased accordingly to the achieved DMR: 21%, 13% and 0% in MR4.0, MR4.5 and MR5.0 respectively, without significant differences.
Our results show that patients with good MR (≥3log) were significantly associated with a lower proportion of cases with LSC presence. When the LSC analysis was performed exclusively in cases with DMR, we observed that the decrease of LSC accompanied the deepness of the molecular response. Since the LSC is highly quiescent, it could be present even in cases with undetectable MR. In our study persistence of LSC in cases with DMR was 16%, indicating that these cells remain despite the MR achieved. This new approach to the study of the LSC could be useful in long-term follow-up and of great importance in the evaluation of molecular recurrence in cases included in discontinuation protocols.
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