Autophagy in Hematological Malignancies: Molecular Aspects in Leukemia and Lymphoma

Hassan Boustani, MSc; Elahe Khodadi, MSc; Minoo Shahidi, PhD

Disclosures

Lab Med. 2021;52(1):16-23. 

In This Article

Abstract and Introduction

Abstract

The organization of the hematopoietic system is dependent on hematopoietic stem cells (HSCs) that are capable of self-renewal and multilineage differentiation to produce different blood cell lines. Autophagy has a central role in energy production and metabolism of the cells during starvation, cellular stress adaption, and removing mechanisms for aged or damaged organelles.

The role and importance of autophagy pathways are becoming increasingly recognized in the literature because these pathways can be useful in organizing intracellular circulation, molecular complexes, and organelles to meet the needs of various hematopoietic cells. There is supporting evidence in the literature that autophagy plays an emerging role in the regulation of normal cells and that it also has important features in malignant hematopoiesis. Understanding the molecular details of the autophagy pathway can provide novel methods for more effective treatment of patients with leukemia. Overall, our review will emphasize the role of autophagy and its different aspects in hematological malignant neoplasms.

Introduction

Autophagy is a vesicular pathway in which the cellular components are moved to autophagosome vesicle and then will degenerate in lysosomes.[1] Autophagy is created in different conditions, such as nutrient- and energy-limiting conditions, endoplasmic reticulum stress, reactive oxygen species (ROS), hormonal imbalance, and exposure to microorganisms.[2] Autophagy plays an important role in cellular renewal of quiescent and differentiated cells, physiological processes, cell survival, and immune responses. This process is defective in inflammatory conditions, infections, cancer, neurodegenerative disorders, and aging.[3]

The results of studies[4] on yeast have revealed autophagy-related genes (ATG) that produce autophagosomes by a multistep process. The role of autophagy is complicated in cancer, depending on the stage, type, and driving oncogene in tumor cells. Study results[5,6] have shown the role of autophagy in tumor formation and metastasis in protection against apoptosis and support of cell survival. Also, the mechanisms involved in the therapy-resistance of tumor cells may occur due to autophagic response to therapy in tumor cells.

Hematopoiesis is a fully coordinated process in which hematopoietic stem pools and high self-renewing precursor cells (HSPCs) can form lymphoid and myeloid lineages. The HSPC pool decreases with aging, which results in a small number of HSPC clones that maintain hematopoiesis; with the decrease in blood-cell diversity, a phenomenon called clonal hematopoiesis occurs. Clonal proliferation in HSPCs that have a specific genetic mutation results in an increased risk of developing blood-based malignant neoplasms (Figure 1).[7]

Figure 1.

The role of autophagy in normal and malignant cells. Normal high self-renewing precursor cells (HSPCs) can form lymphoid and myeloid lineages by autophagy. Aging results in a decrease and in clonal hematopoiesis of HSPCs. Genetic, epigenetic, and autophagy defects make leukemic stem cells (LSCs) in lymphoid and myeloid cells, which result in myeloid and lymphoid leukemias and lymphomas. HSCs indicates hematopoietic stem cells; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome; ALL, acute lymphoid leukemia; CLL, chronic lymphoid leukemia; DLBCL, diffused large-cell B lymphoma; MCL, mantle cell lymphoma; BL, Burkitt lymphoma; MM, multiple myeloma; ALCL, anaplastic large-cell lymphoma; FL, follicular lymphoma.

Stem cell proliferation and differentiation in many tissues, including the hematopoietic system, is associated with dysregulation in malignant neoplasms. Leukemia cells have genetic and epigenetic defects that make them genetically distinct from normal blood cells. Hematopoietic cells are transformed at the stem cell stage and move towards the leukemic form. The initiation of leukemia, its progression, its resistance to treatment, and the recurrence of the disease are due to the proliferation of stem cells that are inherently resistant to conventional chemotherapy treatments.[8] Because leukemic stem cells (LSCs) also maintain minimal residual disease (MRD) and recur after treatment, a targeted approach is needed to eradicate them and provide sustainable treatment to patients.[9]

Early-onset autophagy increases the occurrence of hematological malignant neoplasms and increases the protumoral response that occurs in tumor growth stages by autophagy and in response to treatment modalities.[10] There is some evidence[11] that modulation of autophagy pathways can be a useful and effective therapeutic approach in patients with leukemia. Therefore, in this review, we discuss the autophagy pathway and its different molecular aspects in the development of hematological malignant neoplasms, including myeloid and lymphoid leukemia and lymphoma.

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