Hyperleukocytic Acute Leukemia Circulating Exosomes Regulate HSCs and BM-MSCs.

Yanmei Yang,Jigang He,Yalian Sa,Rongxia Zuo,Haiping He,Xuezhong Gu,Peng Hu

doi:10.1155/2021/9457070

Yanmei Yang, Jigang He + Show 5 more

Open Access

https://doi.org/10.1155/2021/9457070

Copy DOI

Abstract

Hyperleukocytic acute leukemia (HLAL) circulating exosomes are delivered to hematopoietic stem cells (HSCs) and bone marrow mesenchymal stem cells (BM-MSCs), thereby inhibiting the normal hematopoietic process. In this paper, we have evaluated and explored the effects of miR-125b, which is carried by HLAL-derived exosomes, on the hematopoietic function of HSCs and BM-MSCs. For this purpose, we have isolated exosomes from the peripheral blood of HLAL patients and healthy volunteers. Then, we measured the level of miR-125b in exosomes cocultured exosomes with HSCs and BM-MSCs. Moreover, we have used miR-125b inhibitors/mimic for intervention and then measured miR-125b expression and colony forming unit (CFU). Apart from it, HSC and BM-MSC hematopoietic-related factors α-globulin, γ-globulin, CSF2, CRTX4 and CXCL12, SCF, IGF1, and DKK1 expression were measured. Evaluation of the miR-125b and BAK1 targeting relationship, level of miR-125b, and expression of hematopoietic-related genes was performed after patients are treated with miR-125b mimic and si-BAK1. We have observed that miR-125b was upregulated in HLAL-derived exosomes. After HLAL-exosome acts on HSCs, the level of miR-125b is upregulated, reducing CFU and affecting the expression of α-globulin, γ-globulin, CSF2, and CRCX4. For BM-MSCs, after the action of HLAL-exo, the level of miR-125b is upregulated and affected the expression of CXCL12, SCF, IGF1, and DKK1. Exosomes derived from HLAL carry miR-125b to target and regulate BAK1. Further study confirmed that miR-125b and BAK1mimic reduced the expression of miR-125b and reversed the effect of miR-125b mimic on hematopoietic-related genes. These results demonstrated that HLAL-derived exosomes carrying miR-125b inhibit the hematopoietic differentiation of HSC and hematopoietic support function of BM-MSC through BAK1.

Highlights

Hyperleukocytic acute leukemia (HLAL) is a medical emergency of hematological malignancy, which is defined as high white blood cell (WBC) counts exceeding 100 × 109/ L with very high early complications and mortality rate [1].e incidence of HLAL in acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) is about 5–20% and 18.6%, respectively [2]
We have investigated the effects of circulating exosomes from HLAL patients and examined the expression of miRNAs in HLAL-drived exosomes. e main contributions of this article are given as follows: (1) To evaluate and explore the effects of miR-125b, which is carried by HLAL-derived exosomes, on the hematopoietic function of hematopoietic stem cells (HSCs) and bone marrow mesenchymal stem cells (BM-MSCs)
Our study found that HLAL-exo affects the hematopoietic differentiation of HSC and the hematopoietic support function of BM-MSC

Summary

Introduction

Hyperleukocytic acute leukemia (HLAL) is a medical emergency of hematological malignancy, which is defined as high white blood cell (WBC) counts exceeding 100 × 109/ L with very high early complications and mortality rate [1].e incidence of HLAL in acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) is about 5–20% and 18.6%, respectively [2]. Hyperleukocytosis (HL) is a highrisk situation in leukemia, which is associated with leukostasis syndrome, tumour lysis syndrome (TLS), and disseminated intravascular coagulopathy (DIC) It is independently associated with shorter relapse-free survival and a lower response to initial chemotherapy [3, 4]. Leukemia cells induce molecular changes in distinct hematopoietic and nonhematopoietic cell populations in the bone marrow niche [8]. Bone marrow mesenchymal stem cells (BM-MSCs) play a critical role in maintaining normal hematopoiesis and the process of mobilization and homing, and in drug resistance and clinical recurrence, by secreting various cytokines, chemokines, and signaling molecules [10]. AML cells remodel the bone marrow niche leukemia-permissive microenvironment and inhibit hematopoiesis by deriving exosomes to BM-MSCs [13]. Little is known about how HLALderived exosomes effect the HSCs and BM-MSCs

Results

Discussion

Conclusion