TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia

Abstract

SUMMARY Fanconi Anemia (FA) is an inherited DNA repair disorder characterized by progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell (HSPC) attrition. A greater understanding of the pathogenesis of BMF could improve the therapeutic options for FA patients. Using a genome-wide shRNA screen in human FA fibroblasts, we identify transforming growth factor-β (TGF-β) pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-β pathway improves the survival of FA cells and rescues the proliferative and functional defects of HSPCs derived from FA mice and FA patients. Inhibition of TGF-β signaling in FA HSPCs results in elevated homologous recombination (HR) repair with a concomitant decrease in non-homologous end-joining (NHEJ), accounting for the improvement in cellular growth. Together, our results suggest that elevated TGF-β signaling contributes to the BMF in FA by impairing HSPC function, and may be a potential therapeutic target for the treatment of FA.

Induction of TGF-β by Irradiation or Chemotherapy in Fanconi Anemia (FA) Mouse Bone Marrow Ιs Modulated by Small Molecule Radiation Mitigators JP4-039 and MMS350

“…A hyperactive TGF-β response pathway has recently been demonstrated in both FA patients and in animal models of FA (5). The data have suggested the potential value of utilizing a TGF-β signal transduction inhibitor as a therapeutic agent to improve marrow stem cell engraftment in FA patients.…”

“…FA patients have previously been demonstrated to have a hyperactive TGF-β response pathway (5), which may be a major cause of their initial marrow failure leading to anemia, as well as their sensitivity to the regimens used to prepare for bone marrow transplantation (1)(2)(3)(4)(6)(7)(8)(9). FA patients are also susceptible to late post-transplant induction of leukemia and solid tumors (7)(8)(9)(10)(11)(12)(13)(14)(15).…”

Transient Inhibition of Endogenous Transforming Growth Factor- β1 (TGFβ1) in Hematopoietic Stem Cells Accelerates Engraftment and Enhances Multi-Lineage Repopulating Efficiency

“…In summary, these data show marked improvements in HSC transplantation efficiency in experimental animal models and suggests that this approach can be clinic useful in settings of limited donor HSC. Other recent studies have demonstrated that inhibition of endogenous TGFβ1 in human CD34+ cells can substantially reverse the dysfunctions of diabetic lin-CD34+CD45+ stem cells [41] and dysfunctional CD34+ cells isolated from Fanconi anemia patients [42].…”

Reduced Competitive Repopulation Capacity of Multipotential Hematopoietic Stem Cells in the Bone Marrow of Friend Virus-infected Fv2-resistant Mice

“…Assays for the canonical signaling pathway through: (i) SMAD3; (ii) the phospho-ERK pathway or noncanonical pathways; (iii) PI3-Kinase pathway; (iv) p38, JNK-1 pathway; and (v) the RHO-Kinase pathway were carried out, according to published methods for Western blots (12,23). Western blots were carried out three times on three sets of bone marrow from the four treatment groups (virus-infected oruninfected FVB on C57BL/6 mice).…”

“…A recent publication showed that TGF-β hyper-responsiveness of hematopoietic stem cells from Fanconi anemia (Fancd2 -/-) mice exhausts the hematopoietic stem cell compartment, decreases competitive repopulation capacity of stem cells and produces marrow failure (12). Whether Friend virus acted by blocking TGF-β signaling and resulted in expansion of marrow stem cell self-renewal (2) has not been previously investigated.…”