Mitochondrial Fragmentation Triggers Ineffective Hematopoiesis in Myelodysplastic Syndromes

Abstract

Ineffective hematopoiesis is a fundamental process leading to the pathogenesis of myelodysplastic syndromes (MDS). However, the pathobiological mediators of ineffective hematopoiesis in MDS remain unclear. Here, we demonstrated that overwhelming mitochondrial fragmentation in mutant hematopoietic stem cells and progenitors (HSC/P) triggers ineffective hematopoiesis in MDS. Mouse modeling of CBL exon deletion with RUNX1 mutants, previously unreported comutations in patients with MDS, recapitulated not only clinically relevant MDS phenotypes but also a distinct MDS-related gene signature. Mechanistically, dynamin-related protein 1 (DRP1)–dependent excessive mitochondrial fragmentation in HSC/Ps led to excessive reactive oxygen species production, induced inflammatory signaling activation, and promoted subsequent dysplasia formation and impairment of granulopoiesis. Mitochondrial fragmentation was generally observed in patients with MDS. Pharmacologic inhibition of DRP1 attenuated mitochondrial fragmentation and rescued ineffective hematopoiesis phenotypes in mice with MDS. These findings provide mechanistic insights into ineffective hematopoiesis and indicate that dysregulated mitochondrial dynamics could be a therapeutic target for bone marrow failure in MDS. Significance: We demonstrated that excessive mitochondrial fragmentation is a fundamental pathobiological phenomenon that could trigger dysplasia formation and ineffective hematopoiesis in MDS. Our findings provide mechanistic insights into ineffective hematopoiesis and suggest dysregulated mitochondrial dynamics as a therapeutic target for treating MDS. This article is highlighted in the In This Issue feature, p. 1

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

“…In a previous study, AML patients with high FIS1 expression likely to be chemotherapy-resistant and were more frequently M0/M1 FAB subtypes [77]. Similarly, mitochondrial fragmentation and increased Drp1 is also associated with MDS with CBL exon deletion and RUNX1 mutation, promoting dysplasia and impaired granulopoiesis [120]. Additionally, Drp-1-dependent mitochondrial fragmentation is seen in the mesenchymal stromal cells in MDS with iron overload, contributing to cell damage [121].…”

“…In a mouse model with both RUNX1 mutation and CBL exon deletion increased Drp1-dependent mitochondrial fission and ROS production in the tumor cells, leading to impaired granulopoiesis dysplasia and an overall MDS phenotype. These changes were reversible with Drp1 inhibition, making it a promising therapeutic candidate in MDS patients harboring RUNX1 mutation/RUNX1/RUNX1T1 fusion gene [120].…”

Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells

“…We next analyzed the mitochondrial morphology in HSPCs. Alterations in mitochondrial morphology and distribution in HSCs have been previously reported in myelodysplastic syndrome (MDS) and leukemia; mitochondria in HSCs from MDS models diffuse and spread out while mitochondria in leukemic stem cells (LSC) exhibit polarity and are concentrated ( 16 , 17 ). Imaging flow cytometer (IFM) was utilized to calculate mitochondrial area, concentration, and polarity in individual HSPCs.…”

Acquired and hereditary bone marrow failure: A mitochondrial perspective

“…In a mouse model of CBL exon deletion with RUNX1 mutants, that recapitulated clinically relevant MDS phenotypes, HSC and progenitor cells exhibited excessive mitochondrial fragmentation that was caused by enhanced activity of the mitochondrial fission regulator DRP1. The subsequent elevation in ROS production and inflammatory signals promoted the development of dysplasia and impaired granulopoiesis ( 18 ). Other studies have reported abnormal mitochondrial structure, or abnormal mitochondrial biogenesis and mitophagy in BMF, notably in FA.…”

“…Interestingly, several evidence suggest that disruption of mitochondria is another preponderant factor in BMF/MDS development. Abnormal mitochondria have been linked to both acquired and hereditary BMF (18)(19)(20)(21)(22)(23)(24). Patients with MDS have transcriptional, morphological and functional dysregulation of their mitochondria, according to several studies (25)(26)(27)(28).…”