The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

Abstract

For two decades, leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR-ABL1 in a hematopoietic stem cell (HSC) drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukemic events-adding further layers of context and genetic and cellular heterogeneity to AML LSCs that is not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standardof-care therapies and persist in patients, diversify clonally, and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal HSCs. These features may represent Achilles' heels against which novel therapies can be developed. Here, we

Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

“…A related problem is that AML LSC exhibit multiple forms of LSC resistance. [13][14][15][16][17][18][19]82 In line with this notion, AML patients relapse quite frequently after CAR-T or CAR-NK cell therapy. Therefore, one strategy for the future could be to direct the CAR-T or CAR-NK approach Another strategy would be to apply CAR cells early in AML or even in patients with pre-AML conditions (myelodysplastic or myeloproliferative neoplasms) with the hope that LSC are more responsive in these patients than in patients with progressed, secondary, or relapsed AML.…”

“…Another important point is the molecular complexity and the related subclone formation in AML. [15][16][17][18][19] So far, little is known about phenotypic properties of AML LSC. Based on LSC features described above, a surface marker or target can only be considered as being "expressed on AML LSC," when it is detected on most or all CD34 + /CD38 − and most or all CD34 + /CD38 + cells.…”

“…[9][10][11][12][13][14] The LSC concept predicts that any type of targeted therapy or other treatment approach can only be curative when (a) the approach does not only attack the bulk of AML cells but also LSC, (b) all LSC in all subclones of the disease exhibit the target(s), and (c) treatment is independent of or overcomes LSC resistance. [14][15][16][17][18][19] Initial studies suggested that AML LSC reside primarily in a phenotypically more immature, CD34 + /CD38 − /Lin − subset of the AML clones. [9][10][11] However, depending on molecular features, aberration profiles, and the diagnostic subvariant of AML, LSC are also detectable in a (phenotypically) more mature CD34 + /CD38 + subset or even in CD34-negative AML cell subsets.…”

“…20,21 In the past few years, the LSC concept has attracted more and more attention, and a rapidly expanding number of studies have discovered and validated distinct molecular targets and target-pathways in these cells. [9][10][11][12][13][14][15][16][17][18][19] With regard to specific cell therapies and immunotherapies, surface membrane targets are of great interest. In fact, such molecules are increasingly used to establish AML-eradicating approaches.…”

<em>Agaricus blazei</em> extract (FA‑2‑b‑&beta;) induces apoptosis in chronic myeloid leukemia cells

“…Thus, BCR-ABL1 is considered a therapeutic chemotherapy target for CML, using the imatinib class of drugs. However, the main drawback of therapeutic TK inhibitors is the severe side effects exhibited in patients with CML ( 6 ), including cardiovascular, pulmonary, gastrointestinal and endocrine toxicities ( 7 ), as well as development of resistance ( 8 ). Thus, it is essential to investigate alternative agents to minimize the side effects.…”