Abstract
Tyrosine kinase inhibitor treatment of chronic myeloid leukemia (CML) has demonstrated beneficial effects. However, resistance to tyrosine kinase inhibitors and disease relapse are still a challenge for CML therapy. In this study, we analyzed bone marrow samples from 149 CML patients and 15 control donors, and investigated the affect of AF1q on CML cell survival and engraftment in vitro and in vivo. We found that AF1q/MLLT11 expression was significantly upregulated in CML patients, especially in CD34+ CML cells. Elevated AF1q expression was associated with disease progression. Knockdown of AF1q enhanced imatinib sensitivity, induced apoptosis, and suppressed growth in CML cells. Moreover, AF1q deficiency sensitized CD34+ CML cells to imatinib. In contrast, upregulation of AF1q promoted cell survival, protected CML cells from imatinib-induced apoptosis, and increased engraftment of CML cells in vivo. We further identified a positive correlation between AF1q and CD44 expression in chronic phase CML patients and CD34+ CML cells. Importantly, AF1q contributes to imatinib-resistance in CML by regulating the expression of CD44. These findings reveal a novel BCR-ABL-independent pathway, AF1q/CD44, involves imatinib resistance in CML, thus representing a potential therapeutic target for imatinib-resistant CML patients.
Highlights
Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell (HSC) disorder characterized by the t (9;22)(q34;q11) translocation, which results in formation of the fusion oncogene BCR-ABL1,2
We show that knockdown of AF1q by small interfering RNA suppresses cell survival and sensitizes CML cells or CD34+ CML progenitors to IM, whereas elevated AF1q expression contributes to cell growth and protection of CML cells from IM-induced apoptosis
In matched-pair bone marrow samples acquired from three available follow-up CML patients, AF1q expression was increased when patients progressed into accelerated phase (AP) compared to when they were in chronic phase (CP) (Fig. 1b)
Summary
Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell (HSC) disorder characterized by the t (9;22)(q34;q11) translocation, which results in formation of the fusion oncogene BCR-ABL1,2. The BCR-ABL protein has constitutive tyrosine kinase activity that directs HSC differentiation toward myeloid progenitors and differentiated myeloid cells expansion, and is essential for the growth of CML cells[3,4]. The BCR-ABL specific tyrosine kinase inhibitors (TKIs), such as imatinib (IM), are highly effective in the treatment of CML, leading to complete cytogenetic responses (CCyR) in a majority of chronic phase (CP) CML patients[5].
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