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<p>Molecular mechanisms underlying congenital neutropenia in patients with HAX1 deficiency are not clear at the moment. HAX1 deficiency was shown to result in the arrest of neutrophil differentiation. Our studies of the effect of HAX1 deficiency on the proteomic and metabolic profiles of promyelocytic cells have led to the conclusion, supported by specific tests, that fatty acid metabolism is affected in <i>HAX1</i> KO cells. The lipid droplet content is increased in <i>HAX1</i> KO cells, pointing to the accumulation of fatty acids that are not metabolized. Studies of autophagosome function in <i>HAX1</i> WT and KO cells revealed that lipid droplet autophagy is defective at the stage of fusion with the lysosome. Autophagy-dependent generation of free fatty acids is critical for neutrophil differentiation, so HAX1 deficiency that affects normal autophagy of lipids in promyeloblasts should explain differentiation arrest. Moreover, we have demonstrated that HAX1-deficient cells are also compromised in fatty acid uptake.</p>

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Granulocyte differentiation arrest in HAX1-deficient cells, demonstrated in a new in vitro model of a certain phenotypic aspects of Kostmann disease, is caused by ineffective lipid droplet autophagy and fatty acids uptake

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月5日

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  • Maciej Wakula,
  • Milena Jablonowska,
  • Mateusz Chmielarczyk,
  • Leszek Tarnowski,
  • Mariusz Kulinczak,
  • Ewa Sitkiewicz,
  • Bianka Swiderska,
  • Emilia Samborowska,
  • Mariusz Radkiewicz,
  • Mostafa Kianfar,
  • Malgorzata Statkiewicz,
  • Izabela Rumienczyk,
  • Anna Balcerak,
  • Ryszard Konopinski,
  • Alicja Trebinska-Stryjewska,
  • Ewa A. Grzybowska

摘要

Molecular mechanisms underlying congenital neutropenia in patients with HAX1 deficiency are not clear at the moment. HAX1 deficiency was shown to result in the arrest of neutrophil differentiation. Our studies of the effect of HAX1 deficiency on the proteomic and metabolic profiles of promyelocytic cells have led to the conclusion, supported by specific tests, that fatty acid metabolism is affected in HAX1 KO cells. The lipid droplet content is increased in HAX1 KO cells, pointing to the accumulation of fatty acids that are not metabolized. Studies of autophagosome function in HAX1 WT and KO cells revealed that lipid droplet autophagy is defective at the stage of fusion with the lysosome. Autophagy-dependent generation of free fatty acids is critical for neutrophil differentiation, so HAX1 deficiency that affects normal autophagy of lipids in promyeloblasts should explain differentiation arrest. Moreover, we have demonstrated that HAX1-deficient cells are also compromised in fatty acid uptake.