ARID5B regulates fatty acid metabolism and proliferation at the Pre-B cell stage during B cell development

Abstract

During B cell development in bone marrow, large precursor B cells (large Pre-B cells) proliferate rapidly, exit the cell cycle, and differentiate into non-proliferative (quiescent) small Pre-B cells. Dysregulation of this process may result in the failure to produce functional B cells and pose a risk of leukemic transformation. Here, we report that AT rich interacting domain 5B (ARID5B), a B cell acute lymphoblastic leukemia (B-ALL) risk gene, regulates B cell development at the Pre-B stage. In both mice and humans, we observed a significant upregulation of ARID5B expression that initiates at the Pre-B stage and is maintained throughout later stages of B cell development. In mice, deletion of Arid5b in vivo and ex vivo exhibited a significant reduction in the proportion of immature B cells but an increase in large and small Pre-B cells. Arid5b inhibition ex vivo also led to an increase in proliferation of both Pre-B cell populations. Metabolic studies in mouse and human bone marrow revealed that fatty acid uptake peaked in proliferative B cells then decreased during non-proliferative stages. We showed that Arid5b ablation enhanced fatty acid uptake and oxidation in Pre-B cells. Furthermore, decreased ARID5B expression was observed in tumor cells from B-ALL patients when compared to B cells from non-leukemic individuals. In B-ALL patients, ARID5B expression below the median was associated with decreased survival particularly in subtypes originating from Pre-B cells. Collectively, our data indicated that Arid5b regulates fatty acid metabolism and proliferation of Pre-B cells in mice, and reduced expression of ARID5B in humans is a risk factor for B cell leukemia.

Constitutional and acquired genetic variants in ARID5B in pediatric B‐cell precursor acute lymphoblastic leukemia

“…Previous studies have shown that the risk allele lowers ARID5B expression 7 and that dysregulation of this gene affects B-cell hematopoiesis. 12,13 Why this results in increased risk specifically for HeH ALL is not known. A characteristic feature of the HeH subtype is the nonrandom gain of chromosomes, with an extra copy of chromosome 10, that carries ARID5B, being seen in 70% of cases.…”

“…Constitutional single nucleotide polymorphisms (SNPs) in the ARID5B gene at 10q21.2, which codes for a member of the AT‐rich interactive domain (ARID) protein family involved in chromatin‐remodeling, 1,2 are associated with an increased risk of developing childhood B cell precursor acute lymphoblastic leukemia (BCP ALL), particularly of the high hyperdiploid (HeH; 51–67 chromosomes) subtype 3–11 as well as with an increased risk of relapse of pediatric ALL 6,7,9 . Two recent publications have reported that ARID5B expression plays an important role in regulating hematopoiesis at the pre‐B‐stage 12,13 . In a mouse model, Chalise et al 12 showed that deletion of ARID5B led to a significant reduction in immature B cells.…”

“…Furthermore, a decrease in ARID5B expression was observed in leukemic blast cells from BCP ALL patients in comparison with B‐cells from nonleukemic individuals. Also, lower ARID5B expression was associated with decreased survival in BCP ALL patients 12 . Goodings et al 13 found that transgenic mice with overexpression of Arid5b had a reduction in circulating B‐cells, immature and mature B‐cells, mainly driven by a lower lymphocyte count, and a decrease of follicular B cells in the spleen.…”

“…6,7,9 Two recent publications have reported that ARID5B expression plays an important role in regulating hematopoiesis at the pre-B-stage. 12,13 In a mouse model, Chalise et al 12 showed that deletion of ARID5B led to a significant reduction in immature B cells. Furthermore, a decrease in ARID5B expression was observed in leukemic blast cells from BCP ALL patients in comparison with B-cells from nonleukemic individuals.…”

“…Also, lower ARID5B expression was associated with decreased survival in BCP ALL patients. 12 Goodings et al 13 found that transgenic mice with overexpression of Arid5b had a reduction in circulating B-cells, immature and mature B-cells, mainly driven by a lower lymphocyte count, and a decrease of follicular B cells in the spleen.…”