Gata2 noncoding genetic variation as a determinant of hematopoietic stem/progenitor cell mobilization efficiency

Abstract

Germline genetic variants alter the coding and enhancer sequences of GATA2, which encodes a master regulator of hematopoiesis. The conserved murine Gata2 enhancer (+9.5) promotes hematopoietic stem cell (HSC) genesis during embryogenesis. Heterozygosity for a single-nucleotide Ets motif variant in the human enhancer creates a bone marrow failure and acute myeloid leukemia predisposition termed GATA2 deficiency syndrome. The homozygous murine variant attenuates chemotherapy- and transplantation-induced hematopoietic regeneration, hematopoietic stem and progenitor cell (HSPC) response to inflammation, and HSPC mobilization with the therapeutic mobilizer G-CSF. As a Gata2 +9.5 variant attenuated G-CSF-induced HSPC expansion and mobilization, and HSC transplantation therapies require efficacious mobilization, we tested whether variation impacts mechanistically distinct mobilizers or only those operating through select pathways. In addition to affecting G-CSF activity, Gata2 variation compromised IL-8/CXCR2- and VLA-4/VCAM1-induced mobilization. While the variation did not disrupt HSPC mobilization mediated by plerixafor, which functions through CXCR4/CXCL12, homozygous and heterozygous variation attenuated mobilization efficacy of the clinically used plerixafor/G-CSF combination. The influence of non-coding variation on HSPC mobilization efficacy and function is important clinically since comprehensive non-coding variation is not commonly analyzed in patients. Furthermore, our mobilization-defective system offers unique utility for elucidating fundamental HSPC mechanisms.

Stem Cells Collection and Mobilization in Adult Autologous/Allogeneic Transplantation: Critical Points and Future Challenges

“…Despite this, it is common that more than 90% of patients reach the peak of hematopoietic stem cells between the 10th and 20th day of mobilization, regardless of the diagnosis and previous cycles of chemotherapy or radiotherapy [86]. However, it is also a well-established opinion that there is a huge individual difference in reaching this, for reasons that are not yet fully understood, probably of genetic origin [87,88]. In order to accurately determine the optimal timing for initiating stem cell collection, a combination of benchmarks, including best practices or consensus guidelines, should be considered [54,89].…”