Repolarization of HSC attenuates HSCs failure in Shwachman-Diamond syndrome.

Leukemia 2021 Jun

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Shwachman-Diamond syndrome (SDS) is a bone marrow failure (BMF) syndrome associated with an increased risk of myelodysplasia and leukemia. The molecular mechanisms of SDS are not fully understood. We report that primitive hematopoietic cells from SDS patients present with a reduced activity of the small RhoGTPase Cdc42 and concomitantly a reduced frequency of HSCs polar for polarity proteins. The level of apolarity of SDS HSCs correlated with the magnitude of HSC depletion in SDS patients. Importantly, exogenously provided Wnt5a or GDF11 that elevates the activity of Cdc42 restored polarity in SDS HSCs and increased the number of HSCs in SDS patient samples in surrogate ex vivo assays. Single cell level RNA-Seq analyses of SDS HSCs and daughter cells demonstrated that SDS HSC treated with GDF11 are transcriptionally more similar to control than to SDS HSCs. Treatment with GDF11 reverted pathways in SDS HSCs associated with rRNA processing and ribosome function, but also viral infection and immune function, p53-dependent DNA damage, spindle checkpoints, and metabolism, further implying a role of these pathways in HSC failure in SDS. Our data suggest that HSC failure in SDS is driven at least in part by low Cdc42 activity in SDS HSCs. Our data thus identify novel rationale approaches to attenuate HSCs failure in SDS.

Citation

Sachin Kumar, Kalpana J Nattamai, Aishlin Hassan, Amanda Amoah, Rebekah Karns, Cuiping Zhang, Ying Liang, Akiko Shimamura, M Carolina Florian, Ute Bissels, Martha Luevano, Andreas Bosio, Stella M Davies, Medhanie Mulaw, Hartmut Geiger, Kasiani C Myers. Repolarization of HSC attenuates HSCs failure in Shwachman-Diamond syndrome. Leukemia. 2021 Jun;35(6):1751-1762