Defective Sphingolipids Metabolism and Tumor Associated Macrophages as the Possible Links Between Gaucher Disease and Blood Cancer Development

Abstract

There is a rising number of evidence indicating the increased risk of cancer development in association with congenital metabolic errors. Although these diseases represent disorders of individual genes, they lead to the disruption of metabolic pathways resulting in metabolite accumulation or their deficiency. Gaucher disease (GD) is an autosomal recessive sphingolipidosis. It is a rare lysosomal storage disease. A strong correlation between GD and different types of cancers, such as multiple myeloma, leukemia, and hepatocellular carcinoma, has been reported. Common features for all types of GD include spleen and liver enlargement, cytopenia, and a variety of bone defects. Overall, the molecular bases leading to the association of GD and cancers are not clearly understood. Here, we describe the role of ceramides in GD, discuss the potential implications of immune cells activation and show how the disturbances in their metabolism might promote blood cancer development.

Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms

“…Intriguingly, glucosyl-sphingosine (GlcSph), a proinflammatory lysosphingolipid accumulated in Gaucher disease (GD), is the target of auto-antibodies in MGUS and in myeloma [ 34 , 35 , 36 , 37 , 38 ]. GD patients also present with chronic inflammation, with high levels of IL-1β, HGF, IL-8, MIP-1β and TNF-α, and an increased risk of malignancy [ 39 , 40 , 41 , 42 , 43 ]. We investigated whether MPN patients may also present with auto-antibodies directed at GlcSph.…”

“…However, patients may also be asymptomatic, and atypical GD may be diagnosed only late in life. GD patients present with an increased risk of cancer, including hematological malignancy, notably B-cell lymphoma, myeloma and also myeloid neoplasms [ 40 , 41 , 42 , 43 ]. Recent studies have established that GlcSph is a frequent target of both clonal and nonclonal immunoglobulins of GD patients who develop a MGUS or a myeloma, which implies that auto-immune responses to GlcSph do initiate cases of MGUS and myeloma [ 34 , 35 , 36 , 37 , 38 ].…”

“…In GD, germline mutations in the glucocerebrosidase ( GBA ) gene result in the accumulation of glucocerebroside corresponding to the primary accumulated sphingolipid, and its deacylated form, the GlcSph. GD patients may present with various clinical manifestations, including an increased risk of developing blood malignancies, notably MGUS and myeloma [ 39 , 40 , 41 , 42 , 43 ].…”

A case of bony lytic lesions in a patient with Gaucher disease

“…The mechanism by which GD results in increased frequency of plasma cell neoplasms is not well understood. Proposed mechanisms include accumulation of bioactive lipids and cellular immune dysregulation resulting from accumulation of glucosylceramides with aberrant macrophage activity . Interestingly, investigation of a series of GD patients with polyclonal or monoclonal gammopathy demonstrated immunoglobulin reactivity against lysolipids in a large proportion of cases (91% of polyclonal and 78% of monoclonal gammopathies) compared with non‐GD patients with MGUS or plasma cell myeloma (approximately 30%), suggesting a possible role for chronic antigenic stimulation by unmetabolized substrates in the development of GD‐related plasma cell neoplasms …”

Decreased Activity of Blood Acid Sphingomyelinase in the Course of Multiple Myeloma

“…Overall, 25% of patients with symptomatic MM are classified as high-risk patients [3]. Interestingly, MGUS and MM are more frequent in patients with a congenital defect of sphingolipid metabolism [4].…”