IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

Abstract

Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Idarubicin-based standard AML chemotherapy by interfering with the BM stroma-mediated chemoresistance. We report that IMiDs do not exert cytotoxic effects on either non-del5q/5q- AML cells nor BM-MSCs, but they enhance the immunomodulatory properties of BM-MSCs. When combined with AraC/Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of non-del5q/5q- AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide specifically mobilizes non-del5q/5q- AML cells, but not healthy CD34+ cells, to peripheral blood (PB) through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated non-del5q/5q- AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize non-del5q/5q- AML blasts to PB through CXCR4 downregulation, but fail to potentiate AraC/Idarubicin activity in preclinical models of non-del5q/5q- AML.

Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity

“…Two days after, non-adherent cells were collected, washed and stained with an anti-CD19 mAb, 7-AAD and AnnexinV to determine cell apoptosis by FACS. 27 …”

“…Ten-week-old non-obese diabetic Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice (The Jackson Laboratory, Bar Harbor, Maine, USA) were bred and housed under pathogen-free conditions. NSG mice were intratibial (IT)-injected with 1×10 6 NALM6-Luc + cells alone or together with 3×10 5 BM-MSC, 27 followed 4 days later by an intravenous infusion of 4×10 6 CD19-CAR T-cells. Mice were followed up weekly by bioluminescence (BLI) using an in vivo imaging system (Lumina III; Perkin-Elmer, Wlatham, Massachusetts, USA).…”

Targeting CXCR4 in AML and ALL

“…Alternatively, inhibition of downstream CXCR4 signaling could be achieved via downregulation of the receptor. Some previously reported strategies to downregulate CXCR4 include treatment with (i) the small molecule bromodomain and extra-terminal domain-containing (BET) proteolysis-targeting chimera (PRTOAC) ARV-825 ( 155 ), (ii) lenalidomide or pomalidomide ( 156 ), and (iii) small interfering RNA [for review see Wang et al ( 141 )]. Additional pre-clinical studies combining cytotoxic chemotherapy with inhibition of CXCL12 ligation (via a CXCR4/CXCL12 inhibitor) and CXCR4 signaling or expression are warranted.…”

Repurposing of thalidomide and its derivatives for the treatment of SARS-coV-2 infections: Hints on molecular action

“…Transcriptome data of bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells (PBMC) were obtained from BIG Data Center (https://bigd.big.ac.cn/) (Accession ID: CRA002390) 17 . The expression profiles of systemic lupus erythematosus (Accession ID: GSE112087) 18 , bone marrow cells treated with lenalidomide (Accession ID: GSE106748) 19 , lymphoma cells treated with lenalidomide (Accession ID: GSE60618) 20 , CD34 positive cells treated with pomalidomide (Accession ID: GSE144052), MERS infected PBMC (Accession: GSE1739) 21 , lenalidomide treated PBMC (Accession ID: GSE84251) and CC-122 treated lymphoma cells (Accession ID: GSE75420) 22 were procured from GEO and differentially expressed genes (DEG) were identified using limma 23 . Library of Integrated Network-Based Cellular Signatures (iLINCS) is a database which contains the gene expression signatures of more than 21,000 compounds (http://www.ilincs.org/ilincs/).…”