Abstract
Selection of resistant clones following intensive chemotherapy is a common obstacle for cure in many cancers, particularly in acute myeloid leukemia (AML). In AML, clone-specific sensitivity to chemotherapy varies even within the same patient. Multiple mutations and genetic aberrations are associated with clones surviving chemotherapy. The current study explored the role of activated signaling pathways in chemoresistance as a function of cell maturation, reflected by CD34 expression. In-vitro, Kasumi-1 leukemic cell line, sorted by CD34 expression, showed increased apoptosis only in the CD34− subpopulation after exposure to cytosine arabinoside (Ara-C) or daunorubicin. The resistant CD34+ subset demonstrated higher expression of ERK1/2 and BCL-2 proteins than CD34− cells. MEK1/2 inhibition elevated Ara-C ability to induce apoptosis in CD34+ cells, suggesting that MEK1/2-ERK1/2 is surviving signaling, which correlates to cell maturation levels and plays a role in chemoresistance. Deep sequencing of sorted CD34+/− populations, both derived from the same patient samples, demonstrated various subclonal distribution of NPM1, DNMT3A and FLT3-ITD mutations. Interestingly, in these samples, p-ERK levels and apoptosis rates following chemotherapy exposure significantly differed between CD34+/− populations. Hence, clones may be selected due to their ability to escape apoptosis rather than a direct effect of chemotherapy on a specific mutated clone.
Highlights
Clonal selection is a major challenge for curing cancer patients treated with chemotherapy
Kasumi-1, derived from early myeloid stem cells and carrying the t(8:21)[22] was found to express a wider spectrum of CD34 antigens compared to other examined cell lines (Fig. 1a) Kasumi-1 cells were sorted into two fractions exhibiting either very high (CD34+) or very low (CD34-) expression of CD34
CD34+ cells were more likely to exist in the S phase, whereas an increased number of CD34- cells existed in the sub-G1 phase (Fig. 1c), meaning that two distinct subpopulations co-existed within the same cell line
Summary
Clonal selection is a major challenge for curing cancer patients treated with chemotherapy. Minor subclones distinguished from the main clone by various genetic and epigenetic aberrations are capable of surviving the effects of combination therapy that effectively eradicates the majority of cancer cells These surviving subclones may cause a future relapse presenting with more aggressive features. During induction chemotherapy including a combination of cytosine arabinoside (Ara-C) and daunorubicin (DNR) (“7 + 3” induction regimen), used as the first-line therapy, minor leukemic subclones survive and may further contribute to disease progression and/or relapse[1] This clonal selection phenomenon occurs in a vast majority of AML patients[2,3,4], selected subclones originating from different patients do not necessarily share specific mutation combinations. The present study aimed to examine the chemosensitivity of CD34+/− AML subclones during the first days of therapy, based on the expression of CD34, known to be the main marker distinguishing maturation stages of leukemic cells, and to explore differences in the ability of these subclones to escape apoptosis
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