Revista:
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN:
0390-6078
Año:
2023
Vol.:
108
N°:
10
Págs.:
2652 - 2663
Clinical trials have shown that lentiviral-mediated gene therapy can ameliorate bone marrow failure (BMF) in nonconditioned Fanconi anemia (FA) patients resulting from the proliferative advantage of corrected FA hematopoietic stem and progenitor cells (HSPC). However, it is not yet known if gene therapy can revert affected molecular pathways in diseased HSPC. Single-cell RNA sequencing was performed in chimeric populations of corrected and uncorrected HSPC co-existing in the BM of gene therapy-treated FA patients. Our study demonstrates that gene therapy reverts the transcriptional signature of FA HSPC, which then resemble the transcriptional program of healthy donor HSPC. This includes a down-regulated expression of TGF-ß and p21, typically up-regulated in FA HSPC, and upregulation of DNA damage response and telomere maintenance pathways. Our results show for the first time the potential of gene therapy to rescue defects in the HSPC transcriptional program from patients with inherited diseases; in this case, in FA characterized by BMF and cancer predisposition.
Revista:
NATURE MEDICINE
ISSN:
1078-8956
Año:
2023
Vol.:
29
N°:
3
Págs.:
632 - 645
The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-kappa B, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of similar to 500 mice and similar to 1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8(+) T cells with reduced immunosuppressive regulatory T (T-reg) cells, while late MYC acquisition in slow progressors was associated with lower CD8(+) T cell infiltration and more abundant T-reg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8(+) T cells versus T-reg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8(+) T/T-reg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8(+) T cell cytotoxicity or depleting T-reg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.
New experimental models provide much-needed tools for understanding how genetically diverse multiple myeloma progresses and evolves in response to therapy.