Abstract
Though fatty acid oxidation has been shown to be essential for hematopoietic stem cell maintenance, the importance of fatty acid uptake from the bone marrow microenvironment vs. de novo lipogenesis has not been elucidated. The process of de novo lipogenesis begins with the generation of malonyl-CoA from acetyl-CoA and is catalyzed by the enzyme acetyl-CoA carboxylase 1 (ACC1), encoded by Acaca. In leukemia, both ACC1 activation and degradation of ACC1 have been shown to enhance disease progression, suggesting an important role in leukemogenesis. The function of ACC1 in normal hematopoiesis remains unknown. To characterize the role of ACC1 in normal hematopoiesis, we bred mice that harbored an Acaca allele in which exons 22 through 26 were flanked by loxp sites. We crossed these animals to a mouse line harboring the Mx1-Cre transgene, generating Acaca fl/fl; Mx1-Cre + (ACC1 KO) and Acaca fl/fl; Mx1-Cre -(ACC1 WT) mice. Animals were then treated with intraperitoneal poly(I:C) injection to drive Mx1-Cre expression and Acaca excision. By 4-6 weeks after poly(I:C) injection, ACC1 KO animals developed expansion of hematopoietic stem cells and progenitors, including Lineage - Sca-1 +cKit hi (LSK) and the LSK CD48 -CD150 + long-term hematopoietic stem cell (LT-HSC) populations. In addition, these animals developed splenomegaly with extramedullary LSK expansion and enhanced myelopoiesis. ACC1 KO LSKs showed increased cell cycle activity and LT-HSCs demonstrated a reduced quiescent fraction compared to ACC1 WT controls. These data suggest that ACC1 deficiency results in increased cell cycle activity among primitive hematopoietic progenitors and biases cell fate to the myeloid lineage. To further test the impact of ACC1 deletion on LT-HSC function, we established competitive chimerism maintenance assays in which equal numbers of CD45.2 +Acaca fl/fl; Mx1-Cre +or CD45.2 +Acaca fl/fl; Mx1-Cre - bone marrow cells were mixed with CD45.1 + competitor bone marrow and transplanted into lethally irradiated recipient mice. Transplants were then given 8 weeks to establish stable engraftment. After documenting comparable engraftment, 5-poly(I:C) injections were administered every other day. Over the course of 16 weeks of tracking, the ACC1 KO graft showed a significant reduction in trilineage hematopoietic output as indicated by a reduction in B cell, T cell, and myeloid populations in the peripheral blood. After 16 weeks, animals were sacrificed and the LT-HSC compartment was analyzed, showing a significant reduction in ACC1 KO LT-HSCs. Together, these data suggest that the loss of ACC1 significantly impairs the ability of LT-HSCs to maintain long term hematopoiesis in competitive transplants. Collectively, these data are the first report of a critical role for ACC1 in hematopoiesis and LT-HSC function. Mechanistically, in the absence of ACC1, FACS sorted LSK demonstrated increased ATP content compared to WT controls, suggesting an altered metabolic state in these progenitor cells. Further studies are ongoing to determine if these findings are due to an essential function for ACC1 within the context of de novo lipogenesis, or if ACC1 participates in an as of yet uncharacterized tumor suppressive role.
Disclosures
No relevant conflicts of interest to declare.
Metabolic Regulation of Invadopodia and Invasion by Acetyl-CoA Carboxylase 1 and De novo Lipogenesis
