Abstract
Acute lymphocytic leukemia is the most common type of cancer in pediatric individuals. Glucose regulated protein (GRP78) is an endoplasmic reticulum chaperone that facilitates the folding and assembly of proteins and regulates the unfolded protein response pathway. GRP78 has a role in survival of cancer and metastasis and cell-surface associated GRP78 (sGRP78) is expressed on cancer cells but not in normal cells. Here, we explored the presence of sGRP78 in pediatric B-ALL at diagnosis and investigated the correlation with bona fide markers of leukemia. By using a combination of flow cytometry and high multidimensional analysis, we found a distinctive cluster containing high levels of sGRP78, CD10, CD19, and CXCR4 in bone marrow samples obtained from High-risk leukemia patients, which was absent in the compartment of Standard-risk leukemia. We confirmed that sGRP78+CXCR4+ blood-derived cells were more frequent in High-risk leukemia patients. Finally, we analyzed the dissemination capacity of sGRP78 leukemia cells in a model of xenotransplantation. sGRP78+ cells emigrated to the bone marrow and lymph nodes, maintaining the expression of CXCR4. Testing the presence of sGRP78 and CXCR4 together with conventional markers may help to achieve a better categorization of High and Standard-risk pediatric leukemia at diagnosis.
Highlights
Acute lymphocytic leukemia is the most common type of cancer in pediatric individuals
The 78-kDa immunoglobulin heavy chain binding protein BIP/HSPA5, known as glucose regulated protein (GRP78) is an endoplasmic reticulum (ER) resident molecular chaperone that belongs to the Hsp[70] family of heat shock proteins and it is a component of the unfolded protein response (UPR) pathway that plays an important role in ER homeostasis[1,2,3]
We observed a higher proportion of surface associated GRP78 (sGRP78)+ cells coexpressing CD34, CD38 or CD10 in the High-risk group compared to the Standard-risk group, but we found no differences in the proportion of sGRP78+ expressing CD19 (Fig. 2C–F)
Summary
Acute lymphocytic leukemia is the most common type of cancer in pediatric individuals. GRP78 has a role in survival of cancer and metastasis and cell-surface associated GRP78 (sGRP78) is expressed on cancer cells but not in normal cells. We confirmed that sGRP78+CXCR4+ blood-derived cells were more frequent in High-risk leukemia patients. Testing the presence of sGRP78 and CXCR4 together with conventional markers may help to achieve a better categorization of High and Standard-risk pediatric leukemia at diagnosis. The 78-kDa immunoglobulin heavy chain binding protein BIP/HSPA5, known as glucose regulated protein (GRP78) is an endoplasmic reticulum (ER) resident molecular chaperone that belongs to the Hsp[70] family of heat shock proteins and it is a component of the unfolded protein response (UPR) pathway that plays an important role in ER homeostasis[1,2,3]. SGRP78 has been observed in a variety of tumors including glioblastoma, prostate, breast, lung, gastric, colon and leukemia[13,14,15,16,17,18]
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