In Vitro models of leukemia development: the role of very small leukemic stem-like cells in the cellular transformation cascade

Abstract

Recent experimental findings indicate that cancer stem cells originate from transformed very small embryonic-like stem cells. This finding represents an essential advancement in uncovering the processes that drive the onset and progression of cancer. In continuously growing cell lines, for the first time, our team's follow-up research on leukemia, lung cancer, and healthy embryonic kidney cells revealed stages that resembles very small precursor stem cells. This review explores the origin of leukemic stem-like cells from very small leukemic stem-like cells establish from transformed very small embryonic-like stem cells. We explore theoretical model of acute myeloid leukemia initiation and progresses through various stages, as well basing the HL60 cell line, present its hierarchical stage development in vitro, highlighting the role of these very small precursor primitive stages. We also discuss the potential implications of further research into these unique cellular stages for advancing leukemia and cancer treatment and prevention.

Keywords: A549; HL60; acute myeloid leukemia development in vitro; cellular transformations; very small leukemic stem-like cells; very small progenitor and precursor stem cells.

FIGURE 1

Lifetime Development of Primitive Stem Cell Precursors and Progenitors. Abbreviations: CPCs, cardiac precursor cells; CD133+ PSCs, CD133+ precursor cells; EcPCs, ectodermal progenitor cells; EnthPC, endothelial progenitor cells; EnPCs, endodermal progenitor cells; EpidPCs, epidermal precursor cells; ESCs, embryonic stem cells; HePCs, hepatic precursor cells; HPC, hematopoietic precursor cells; ICM, inner cell mass; LT-HSCs, long-term hematopoietic stem cells; MdPCs, mesoderm progenitor cells; MIAMICs, marrow-isolated adult multilineage inducible cells; MsPCs, endothelial progenitor cells; MUSECs, multilineage-differentiating stress enduring cells; NPCs, neural precursor cells; PGCs, primordial germ cells; PPCs, pancreatic progenitor cells; SpLCs, spore-like cells; VSELSCs, very small embryonic-like stem cells.

FIGURE 2

A 3D illustration depicting early stages of human development. Stages of development, progressing downstream from the upper left corner: fertilized egg, zygote, 2-cell stage, 4-cell stage, 8-cell stage, morula (16–32 cells), early blob, late blob, early blastocyst (blastocoel fill <50%), 1_blastocyst (blastocoel fill >50%), 2_blastocyst (blastocoel fill >50%), expanded blastocyst, early gastrula, gastrula. The illustrations were created by graphic artist Mr. Tobiasz Sosnowski, inspired by time-lapse microscopy featured on Iwata et al. (2014) as well on TheDeepSci YouTube channel (accessed 20.11.2024).

FIGURE 3

AML initiation and transmission. Disease initiation can occur spontaneously or through pathogenic transmission. The first mutation triggering disease or pathogenicity could have arisen earlier than presented, possibly during the formation of EpibCs from ESCs, or later at the stage of oligopotent progenitors (lacking SD) derived from HSCs/MPPs or P_HSCs/P_MPPs. Disease can independently initiate at various stages. Very small leukemic-like stem cells (VSLSLCs), positioned at the top of the hierarchical development of the HL60 cell line, may originate from M_VSELSCs, M_HPCs, or LT-LSCs. The hypothetical M_HPCs may represent a malignant stage, resembling early progenitors or tissue-specific precursors. The model considers MdSCs arising from VSELSCs or directly from EpibSCs. LT-HSCs, P_LT-HSCs, and LT-LSCs may originate from MdSCs, VSELSCs, or an intermediate hematopoietic precursor not shown in the model. Prefixes denote: M_ for malignancy, P_ for pathogenic. Abbreviations: EpibCs epiblast cells; HSCs, hematopoietic stem cells; HPCs, hematopoietic precursor cells (Anjos-Afonso and Bonnet, 2023); LSCs, leukemic stem cells; MPPs, multipotent progenitor cells; ST-HSCs short-term hematopoietic stem cells; ST-LSCs, short-term leukemic stem cells; LT-HSCs long-term hematopoietic stem cells; LT-LSCs, long-term leukemic stem cells; VSELSCs, very small embryonic-like stem cells.