Author: Kuo, Ya-Huei ; Marcucci, Guido ; Qiao, Junjing ; Hoang, Dinh Hoa ; Su, Yu-Lin ; Pichiorri, Flavia ; Zheng, Yi ; Ghoda, Lucy ; Wang, Huafeng ; Han, Anjia ; Zhao, Dandan ; Feng, Yuxin ; Dorrance, Adrianne ; Yoshimura, Akihiko ; Nguyen, Le Xuan Truong ; Jovanovic-Talisman, Tijana ; Brehove, Matthew ; Chen, Zhen ; Perrotti, Danilo ; Kortylewski, Marcin ; Jin, Jie ; Carlesso, Nadia ; Li, Ling ; Frankhouser, David E ; Kuo, Calvin J ; Stein, Anthony ; Abundis, Christina ; Rockne, Russell C ; Caligiuri, Michael A ; Zhang, Bin

AbstractBackgroundDuring acute myeloid leukemia (AML) growth, the bone marrow (BM) niche acquires significant vascular changes that can be offset by therapeutic blast cytoreduction. The molecular mechanisms of this vascular plasticity remain to be fully elucidated. Herein, we report on the changes that occur in the vascular compartment of the FLT3-ITD+ AML BM niche pre and post treatment and their impact on leukemic stem cells (LSCs).MethodsBM vasculature was evaluated in FLT3-ITD+ AML models (MllPTD/WT/Flt3ITD/ITD mouse and patient-derived xenograft) by 3D confocal imaging of long bones, calvarium vascular permeability assays, and flow cytometry analysis. Cytokine levels were measured by Luminex assay and miR-126 levels evaluated by Q-RT-PCR and miRNA staining. Wild-type (wt) and MllPTD/WT/Flt3ITD/ITD mice with endothelial cell (EC) miR-126 knockout or overexpression served as controls. The impact of treatment-induced BM vascular changes on LSC activity was evaluated by secondary transplantation of BM cells after administration of tyrosine kinase inhibitors (TKIs) to MllPTD/WT/Flt3ITD/ITD mice with/without either EC miR-126 KO or co-treatment with tumor necrosis factor alpha (TNFα) or anti-miR-126 miRisten.ResultsIn the normal BM niche, CD31+Sca-1high ECs lining arterioles have miR-126 levels higher than CD31+Sca-1low ECs lining sinusoids. We noted that during FLT3-ITD+ AML growth, the BM niche lost arterioles and gained sinusoids. These changes were mediated by TNFα, a cytokine produced by AML blasts, which induced EC miR-126 downregulation and caused depletion of CD31+Sca-1high ECs and gain in CD31+Sca-1low ECs. Loss of miR-126high ECs led to a decreased EC miR-126 supply to LSCs, which then entered the cell cycle and promoted leukemia growth. Accordingly, antileukemic treatment with TKI decreased the BM blast-produced TNFα and increased miR-126high ECs and the EC miR-126 supply to LSCs. High miR-126 levels safeguarded LSCs, as shown by more severe disease in secondary transplanted mice. Conversely, EC miR-126 deprivation via genetic or pharmacological EC miR-126 knock-down prevented treatment-induced BM miR-126high EC expansion and in turn LSC protection.ConclusionsTreatment-induced CD31+Sca-1high EC re-vascularization of the leukemic BM niche may represent a LSC extrinsic mechanism of treatment resistance that can be overcome with therapeutic EC miR-126 deprivation.Graphic abstract

01 Oct 2021·Clinical and Translational MedicineQ2 · MEDICINE

Targeting miR‐126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells

Q2 · MEDICINE

ArticleOA

Author: Marcucci, Guido ; Jin, Jie ; McDonald, Tinisha ; Wu, Herman ; Dong, Dan ; Wang, Huafeng ; Zhang, Bin ; Zhao, Dandan ; Li, Ling ; Luo, Yingwan ; Sun, Jie ; Tong, Hongyan ; Yao, Yiyi ; Pichiorri, Flavia ; Stein, Anthony S. ; Carlesso, Nadia ; Kuo, Ya‐Huei ; Al Malki, Monzr M. ; Li, Xia

AbstractBackgroundMyelodysplastic syndrome (MDS) arises from a rare population of aberrant hematopoietic stem and progenitor cells (HSPCs). These cells are relatively quiescent and therefore treatment resistant. Understanding mechanisms underlying their maintenance is critical for effective MDS treatment.MethodsWe evaluated microRNA‐126 (miR‐126) levels in MDS patients’ sample and in a NUP98‐HOXD13 (NHD13) murine MDS model along with their normal controls and defined its role in MDS HSPCs’ maintenance by inhibiting miR‐126 expression in vitro and in vivo. Identification of miR‐126 effectors was conducted using biotinylated miR‐126 pulldown coupled with transcriptome analysis. We also tested the therapeutic activity of our anti‐miR‐126 oligodeoxynucleotide (miRisten) in human MDS xenografts and murine MDS models.ResultsmiR‐126 levels were higher in bone marrow mononuclear cells from MDS patients and NHD13 mice relative to their respective normal controls (P < 0.001). Genetic deletion of miR‐126 in NHD13 mice decreased quiescence and self‐renewal capacity of MDS HSPCs, and alleviated MDS symptoms of NHD13 mice. Ex vivo exposure to miRisten increased cell cycling, reduced colony‐forming capacity, and enhanced apoptosis in human MDS HSPCs, but spared normal human HSPCs. In vivo miRisten administration partially reversed pancytopenia in NHD13 mice and blocked the leukemic transformation (combination group vs DAC group, P < 0.0001). Mechanistically, we identified the non‐coding RNA PTTG3P as a novel miR‐126 target. Lower PTTG3P levels were associated with a shorter overall survival in MDS patients.ConclusionsMiR‐126 plays crucial roles in MDS HSPC maintenance. Therapeutic targeting of miR‐126 is a potentially novel approach in MDS.

Nature CommunicationsQ1 · CROSS-FIELD

Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance

Q1 · CROSS-FIELD

ArticleOA

Author: Kuo, Ya-Huei ; Carnahan, Emily ; Chen, Wei ; Qi, Jing ; Wu, Xiwei ; Nguyen, Le Xuan Truong ; Cai, Qi ; Zhao, Dandan ; Marcucci, Guido ; Cook, Guerry J ; Dong, Haojie ; Kortylewski, Marcin ; Li, Man ; Li, Ling ; Zhang, Lianjun ; Wu, Dijiong ; Hua, Wei-Kai ; Zhang, Bin ; Hoang, Dinh Hoa ; Swiderski, Piotr ; He, Xin ; Chen, Ying-Chieh ; Brewer, Casey J ; Li, Shu ; Rockne, Russell C

AbstractAcute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that theCBFB-MYH11 (CM)fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduces AML rate and extends survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. The combination of miRisten with chemotherapy further enhances the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a therapeutic approach for inv(16) AML.

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Indication	Highest Phase	Country/Location	Organization	Date
Adult Acute Myeloblastic Leukemia	Preclinical	US	City of Hope National Medical Center	12 Dec 2022
Philadelphia chromosome positive chronic myelogenous leukemia	Preclinical	US	City of Hope National Medical Center	12 Dec 2022

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