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. 2024 May 1;109(5):1603-1607.
doi: 10.3324/haematol.2023.284358.

Efficacy of combined low-dose ruxolitinib and cyclosporine in murine immune bone marrow failure

Xingmin Feng  1 , Ash Lee Manley  2 , Zhijie Wu  2 , Haoran Li  2 , Shouguo Gao  2 , Jibran Durrani  2 , Nidhi Aggarwal  2 , Hiroki Mizumaki  2 , Jichun Chen  2 , Neal S Young  2 , Emma M Groarke  2
Affiliations

Efficacy of combined low-dose ruxolitinib and cyclosporine in murine immune bone marrow failure

Xingmin Feng et al. Haematologica. .
No abstract available

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Figures

Figure 1.
Figure 1.
Hematoxicity of ruxolitinib in normal mice. (A) Peripheral white blood cell (WBC), neutrophil (NEU), red blood cell (RBC), hemoglobin (HGB), platelet (PLT), lymphocyte (LYM) counts and CD4 and CD8 percentages during 16 weeks. (B) Total bone marrow (BM) cell numbers, Lin-Sca-1+CD117+ (KSL), myeloid progenitor (MP), and common lymphoid progenitor cell (CLP) numbers in the BM at 16 weeks. (C) Colony forming unit (CFU) assay with BM cells at 16 weeks. (D) Irradiation protection assay with ruxolitinib (RUX)-treated or normal control (CON) donor BM cells at 16 weeks at 1:128 dilution to transplant into lethally irradiated CByB6F1 recipient mice. Survival of recipients was monitored and recorded for 30 days. (E) RNA sequencing: multidimensional scaling plot of LinCD117+ cells from RUX-treated mice at 16 weeks and from CON mice. Data are available under GEO series accession number GSE240867. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001. Log-FC: log fold change.
Figure 2.
Figure 2.
Therapeutic effects of low-dose ruxolitinib, ruxolitinib, and ruxoli-tinib plus ruxolitinib combination on murine immune bone marrow failure. (A) In order to induce bone marrow failure (BMF), 8-week old female CByB6F1 mice were pre-irradiated at 5 Gys total body irradiation (TBI) and infused with 5×106 lymph node (LN) cells/ mouse from C57BL/6 female donors. BMF mice were untreated (BMF), or were treated with low-dose ruxolitinib (RUX, 15 mg/kg gavage twice daily, 5 days/ week for 2-3 weeks, Incyte Corporation, Wilmington, DE) or low-dose cyclosporine A (CsA, 25 mg/kg i.p. once daily, 5 days/week for 2 weeks, Perrigo, Minneapolis, MN) monotherapy, or RUX and CsA combination therapy (RUX+CsA). All treatments started at day 3 following LN infusion. Animals were bled and euthanized at 2 weeks for cellular analyses, or were kept for 12 weeks to monitor survival. (B) Mice were bled at day 14 after LN cell infusion to analyze white blood cells (WBC), neutrophils (NEU), red blood cells (RBC), and platelets (PLT). (C) In one study (N=5, 8, 8, 10 for BMF, CsA, RUX, and RUX+CsA groups), mice were euthanized at day 14 and BM cells were extracted from bilateral tibiae and femurs to analyze BM cell counts, residual BM cell counts (RBM, BM cells excluding T cells), and proportions of CD4+ T cells, CD8+ T cells, apoptosis and viability of RBM. (D) In another study (N=5, 7, 8, and 10 for BMF, CsA, RUX, and RUX+CsA groups), mice were monitored for 12 weeks after 3-week treatment to record animal survival. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001.
Figure 3.
Figure 3.
RNA sequencing of bone marrow T cells from untreated and treated bone marrow failure mice. Bone marrow (BM) CD4+ and CD8+ T cells were sorted from mice (N=5, 8, 8, 10 for bone marrow BM failure [BMF], cyclosporine A [CsA], ruxolitinib [RUX], and RUX+CsA groups) at 2 weeks, and pooled into 3 samples/group. RNA was extracted from pooled samples and applied to RNA sequencing. (A) CD8+ transcriptome distribution of untreated BMF, RUX, CsA, and RUX+CsA-treated BMF mice in multidimensional scale plot. (B) Top gene sets identified by Genomatrix Generanker to be downregulated in BM infiltrated CD8+ T cells from RUX+CsA-treated mice, compared to those from untreated BMF control mice. (C) Gene set enrichment analysis of CD8+ T cells in RUX+CsA versus untreated BMF. NES: normalized enrichment score. (D) CD4+ transcriptome distribution of untreated BMF, RUX, CsA, and RUX+CsA-treated BMF mice in multidimensional scale plot, and heat map of MHC-II genes downregulated in BM infiltrated CD4+ T cells from RUX+CsA-treated versus untreated BMF control mice. A red-blue color scale depicts gene expression levels (red indicates high, blue low). Data are available under GEO series accession number GSE240867.
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