CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

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-ABLindependent 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.

Tyrosine Kinase Inhibitor Therapy Discontinuation for Patients with Chronic Myeloid Leukaemia in Clinical Practice

“…It is possible that gradual TKI withdrawal might provoke hitherto quiescent leukaemic stem cells (LSC) into a more proliferative state in which they may become vulnerable to the TKI, thus lowering the LSC burden at subsequent TKI cessation. The kinetics of residual leukaemia during de-escalated TKI doses or after stopping are difficult to study, since by definition there is very little disease present, though recent data on ten patients in the DESTINY study suggest that lower marrow baseline levels of cells positive for CD93, a potential LSC marker, may predict a better RFS [32]. An alternative possibility is that gradual TKI withdrawal in some way coerces the immune system to respond to residual leukaemia.…”

Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future

“…The expression of certain markers characterizes CML LSC compared to their normal counterpart, the HSC, although this expression may be specific for the disease phase. These include: (a) the sialic acid receptor CD33, which was expressed in CP LSC but only variably in BP LSC [ 23 ], (b) the scavenger receptor CD36, expressed on primitive CML cells with decreased imatinib sensitivity [ 24 ] and on BC LSC in proximity to adipose tissue, whereby it mediates fatty acid uptake and oxidation [ 25 ], (c) the dipeptidylpeptidase IV CD26, which cleaves stromal-derived factor (SDF)1- and, thereby, impairs the SDF-1 - C-X-C chemokine receptor type (CXCR)4-axis leading to an altered response to tyrosine kinase inhibitors (TKIs) [ 26 , 27 ], (d) the lectin transmembrane receptor CD93, which labels a population with increased stem cell characteristics, robust engraftment in xenotransplantation models and correlation with relapse upon TKI withdrawal [ 28 ], (e) the interleukin-1 receptor accessory protein (IL1RAP) [ 27 , 29 ], (f) the interleukin-2 receptor α CD25 [ 30 ] and (g) the interleukin 3 receptor subunit (CD123), a known marker for acute myeloid leukemia stem cells, but also CP and BP LSC [ 31 ]. …”

“…(d) the lectin transmembrane receptor CD93, which labels a population with increased stem cell characteristics, robust engraftment in xenotransplantation models and correlation with relapse upon TKI withdrawal [ 28 ],…”

Transitional dynamics of cancer stem cells in invasion and metastasis

“…Reports state that commonly used chemotherapeutic agents and radiotherapy also accelerate the dynamic transition between non-tumorigenic to tumorigenic state [ 54 , 58 , 59 ]. Despite targeted therapeutic approaches in the treatment of chronic myeloid leukemia (CML), BCR-ABL-independent mechanisms seem to exist which sustain the survival of leukemic stem cells (LSCs) as minimal residual disease or persister cells with increased stem cell characteristics and quiescence [60] . Chronic inflammation and tumor necrosis factor α (TNFα), the major proinflammatory cytokine was found to induce malignant growth and stemness phenotype in HPV-infected oral cancer cells [61] .…”