Abstract
Haematopoiesis is a tightly orchestrated process where a pool of hematopoietic stem and progenitor cells (HSPCs) with high self-renewal potential can give rise to both lymphoid and myeloid lineages. The HSPCs pool is reduced with ageing resulting in few HSPC clones maintaining haematopoiesis thereby reducing blood cell diversity, a phenomenon called clonal haematopoiesis. Clonal expansion of HSPCs carrying specific genetic mutations leads to increased risk for haematological malignancies. Therefore, it comes as no surprise that hematopoietic tumours develop in higher frequency in elderly people. Unfortunately, elderly patients with leukaemia or lymphoma still have an unsatisfactory prognosis compared to younger ones highlighting the need to develop more efficient therapies for this group of patients. Growing evidence indicates that macroautophagy (hereafter referred to as autophagy) is essential for health and longevity. This review is focusing on the role of autophagy in normal haematopoiesis as well as in leukaemia and lymphoma development. Attenuated autophagy may support early hematopoietic neoplasia whereas activation of autophagy in later stages of tumour development and in response to a variety of therapies rather triggers a pro-tumoral response. Novel insights into the role of autophagy in haematopoiesis will be discussed in light of designing new autophagy modulating therapies in hematopoietic cancers.
Highlights
Macroautophagy—Janus-Faced Role in CancerMacroautophagy is a vesicular pathway through which cellular components are sequestered into a double membrane vesicle called the autophagosome and Cells 2019, 8, 103; doi:10.3390/cells8020103 www.mdpi.com/journal/cellsCells 2019, 8, 103 delivered to lysosomes for degradation (Figure 1) [1]
Haematopoiesis is a tightly orchestrated physiological process that leads to the generation of all blood cells from a small population of hematopoietic stem cells (HSCs) [22]
Autophagy is involved in the degradation of certain Acute Myeloid Leukaemia (AML) oncoproteins such as PML-RARA and FLT3-ITD [273,307] but not AML1-ETO [301]. These results demonstrate that autophagy can selectivity eliminate oncoproteins through mechanisms that warrant further investigation
Summary
Macroautophagy ( autophagy) is a vesicular pathway through which cellular components are sequestered into a double membrane vesicle called the autophagosome and . Depending on the stimulus and context, autophagy can sequester bulk cytoplasmic components non-selectively or specific cargoes selectively with the help of autophagy-receptors [3]. Cells 2019, 7, x of cytotoxic damaged organelles and proteins [5]. The autophagosomal membranemembrane expands to sequester sequester cytoplasmic cargoes and to form a vesicle named the autophagosome. This step requires cytoplasmic cargoes and to form a vesicle named the autophagosome This step requires two two ubiquitin-like conjugation systems, ATG5-ATG12/ATG16. Autophagy adaptors drive the cargoes ubiquitin-dependent and -independent mechanisms. Autophagy adaptors drive the cargoes to to the the autophagosomal membrane by binding to LC3/GABARAP-PE through their.
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