Leukemic Stem Cell: A Mini-Review on Clinical Perspectives

Abstract

Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.

Keywords: clinical relapse; drug resistance; hematopoietic stem cells; leukemia stem cell; molecular biomarkers.

Figure 1

Pathways of malignancy in hematopoiesis and its characteristics. Aging and exposure to hazardous environmental agents lead to accumulation of DNA damage and mutations in hematological precursor cells, inducing a pre-leukemic stem cell (pre-LSC) phenotype. Pre-LSCs acquire proliferation advantages over normal hematopoietic stem cells (HSCs) due to mutations in genes such as DNA methyltransferase 3 alpha (DNMT3a), but still retain their capacity to promote normal hematopoiesis. However, further malignant characteristics acquired over the years may tip these cells into a proper leukemic stage. The transformation of pre-LSCs may happen through cell-specific processes, such as epigenetic modulation or new acquired mutations, or through interactions between these cells and their microenvironment, through changes in the normal growth and survival signaling pathways or due to interactions with dysfunctional stromal or mesenchymal cells that are also present in the bone marrow. After malignancy onset, leukemic stem cells (LSC) may present a variety of karyotype rearrangements, such as BCR-ABL or FLT3-ITD, that determine their malignant characteristics and tend to present immunophenotyping profiles that still resemble normal HSCs, such as CD34⁺38^-, while also overexpressing a cohort of cell-surface antigens that are highly variable between patients and even among different cell populations in the same patient.