Hematopoietic stem cells and retroviral infection

Abstract

Retroviral induced malignancies serve as ideal models to help us better understand the molecular mechanisms associated with the initiation and progression of leukemogenesis. Numerous retroviruses including AEV, FLV, M-MuLV and HTLV-1 have the ability to infect hematopoietic stem and progenitor cells, resulting in the deregulation of normal hematopoiesis and the development of leukemia/lymphoma. Research over the last few decades has elucidated similarities between retroviral-induced leukemogenesis, initiated by deregulation of innate hematopoietic stem cell traits, and the cancer stem cell hypothesis. Ongoing research in some of these models may provide a better understanding of the processes of normal hematopoiesis and cancer stem cells. Research on retroviral induced leukemias and lymphomas may identify the molecular events which trigger the initial cellular transformation and subsequent maintenance of hematologic malignancies, including the generation of cancer stem cells. This review focuses on the role of retroviral infection in hematopoietic stem cells and the initiation, maintenance and progression of hematological malignancies.

Figure 1

Hematopoiesis and retroviral infection: CD34⁺ hematopoietic stem cells (HSCs) can undergo self-renewal as well as undergoing maturation to give rise to common lymphoid progenitor (CLP) and common myeloid progenitor (CMP) cells, which serve as precursors to all lymphoid and myeloid cells respectively. HSCs as well as other lineage specific progenitors are permissive for infection by a variety of murine and human retroviruses including HIV-1 and HTLV-1.

Figure 2

Generation of Leukemic Stem Cells. Three hypotheses have been proposed that lead to the development of leukemic stem cells (LSC/CSC): (A) LSC/CSC might arise from either a hematopoietic stem cell (HSC), hematopoietic progenitor cell (HPC), committed lymphoid progenitor (CLP) or committed myeloid progenitor (CMP), (B) from a multipotent HSC or HPC into LSC/CSC through a single transformation event or, (C) from HSC or HPCs through a series of transformation events initiated by the generation of a pre-LSC/CSC.

Figure 3

The "Two-Hit" Model of Retrovirus-Induced Leukemogenesis. (A) HTLV-1 infection of CD34⁺ hematopoietic progenitor and stem cells (HP/HSCs) leads to the development of Adult T-cell leukemia/lymphoma (ATLL). (B) FLV infection of erythroid progenitors leads to erythroleukemia. (C) M-MuLV infection of pro-T cells leads to T-cell lymphoma. The dotted line indicates the separation between the early and late phase of infection.

Figure 4

The Role of HTLV-1 Infection of HSCs: Potential Mechanisms for Generation of an Infectious Leukemic Stem Cell (ILSC/ICSC). HTLV-1 infection and subsequent Tax1 expression can lead to either cell cycle arrest or generation of pre-leukemic stem cells (pre-LSC/CSC) from infected CD34⁺ hematopoietic progenitor and stem cells (HP/HSCs).