Abstract:
:The introduction of BCR-ABL tyrosine kinase inhibitors has revolutionized the treatment of chronic myeloid leukemia (CML). A major clinical aim remains the identification and elimination of low-level disease persistence, termed "minimal residual disease". The phenomenon of disease persistence suggests that despite targeted therapeutic approaches, BCR-ABL-independent mechanisms exist which sustain the survival of leukemic stem cells (LSCs). Although other markers of a primitive CML LSC population have been identified in the preclinical setting, only CD26 appears to offer clinical utility. Here we demonstrate consistent and selective expression of CD93 on a lin-CD34+CD38-CD90+ CML LSC population and show in vitro and in vivo data to suggest increased stem cell characteristics, as well as robust engraftment in patient-derived xenograft models in comparison with a CD93- CML stem/progenitor cell population, which fails to engraft. Through bulk and single-cell analyses of selected stem cell and cell survival-specific genes, we confirmed the quiescent character and demonstrate their persistence in a population of CML patient samples who demonstrate molecular relapse on TKI withdrawal. Taken together, our results identify that CD93 is consistently and selectively expressed on a lin-CD34+CD38-CD90+ CML LSC population with stem cell characteristics and may be an important indicator in determining poor TKI responders.
journal_name
Leukemiajournal_title
Leukemiaauthors
Kinstrie R,Horne GA,Morrison H,Irvine D,Munje C,Castañeda EG,Moka HA,Dunn K,Cassels JE,Parry N,Clarke CJ,Scott MT,Clark RE,Holyoake TL,Wheadon H,Copland Mdoi
10.1038/s41375-019-0684-5subject
Has Abstractpub_date
2020-06-01 00:00:00pages
1613-1625issue
6eissn
0887-6924issn
1476-5551pii
10.1038/s41375-019-0684-5journal_volume
34pub_type
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