Therapeutic targeting of acute myeloid leukemia stem cells

Abstract

For more than 50 years, investigators have considered a malignant stem cell as the potential origin of and a key therapeutic target for acute myeloid leukemia (AML) and other forms of cancer. The nature and existence of tumor-initiating cells for leukemia and other malignancies have long been the subject of intense and rigorous study; indeed, the promise of the potential to eradicate such cells is clear. However, until recently, deficiencies in our understanding of the nature of these cell populations, coupled with a limited ability to therapeutically exploit their weaknesses, have been limiting factors in realizing the goal of targeting leukemic stem cells (LSCs). Exciting new insights into the fundamental underpinnings of LSCs are now being made in an era in which drug development pipelines offer the potential to specifically target pathways of significance. Therefore, the focus in this new era, characterized by the confluence of understanding LSCs and the ability to target them, is shifting from "if it can be done" to "how it will be done." Moving from a theoretical stage to this hopeful era of possibilities, new challenges expectedly arise, and our focus now must shift to determining the best strategy by which to target LSCs, with their well-documented heterogeneity and readily evident intra- and interpatient variability. The purpose of this review is therefore both to summarize the key scientific findings pertinent to AML LSC targeting and to consider methods of clinical evaluation that will be most effective for identifying successful LSC-directed therapies.

The cell of origin and the leukemia stem cell in acute myeloid leukemia

“…Despite these difficulties, which make LSCs appear as fast moving targets for therapy, the benefits of LSC‐targeted therapies are so enticing that great efforts are undertaken to identify properties that distinguish LSCs from HSCs and which can be exploited to develop a LSC‐targeted therapies. Examples for such LSC specific properties include LSC‐specific antigens like CD123 or metabolic vulnerabilities like their greater dependence on the unfolded protein response pathway, increased oxidative stress, or greater reliance on oxidative phosphorylation and greater activation of stress response pathways like NF‐kB signalling …”

“…Examples for such LSC specific properties include LSC-specific antigens like CD123 or metabolic vulnerabilities like their greater dependence on the unfolded protein response pathway, increased oxidative stress, or greater reliance on oxidative phosphorylation and greater activation of stress response pathways like NF-kB signalling. 51 2 | THE CELL OF ORIGIN OF MYELOID LEUKEMIA As stated above, the COL (cell of origin of leukemia) is defined as the non-malignant cell that acquires the transforming mutations, whereas the LSC (leukemia stem cell) is defined as the transformed cell that has unlimited self-renewal, is able to sustain the leukemia and to initiate a leukemia when transplanted to a new host. Thus, the LSC will be closely related but will not be identical to the COL. Identifying the COL and understanding the properties of the COL is not only critical to understand the origin of leukemia but also for understanding the biology of the LSC.…”

Not just a marker: CD34 on human hematopoietic stem/progenitor cells dominates vascular selectin binding along with CD44

“…Future studies using this glycoform of the protein as a target for the generation of mAbs may help to identify and target leukemic stem cells in the treatment of leukemia. 86,87 CD34 marker expression in AML is reported to be associated with poor prognosis and apoptosis-resistance markers. [88][89][90] Interestingly, CD34 fractions derived from AML samples with higher percentages of CD34 cells are more resistant to apoptosis than those derived from samples with a low CD34 percentage.…”

Metabolic underpinnings of leukemia pathology and treatment

“…Glutamine utilization may also be required for pyrimidine synthesis, which represents an additional target for AML . Taken together, these studies have defined a viable therapeutic strategy to eliminate drug‐resistant cells by targeting FLT3 signaling in combination with glutamine metabolism and redox balance to treat AML (Gregory bioRxiv 2018) …”