Integrin α7 and Extracellular Matrix Laminin 211 Interaction Promotes Proliferation of Acute Myeloid Leukemia Cells and Is Associated with Granulocytic Sarcoma.

Nobuhiko Kobayashi,Norifumi Tsukamoto,Akihiko Yokohama,Tsukasa Oda,Makiko Takizawa,Yuki Murakami,Kazuki Honma,Yuko Kuroda,Hirokazu Murakami,Rei Ishihara,Kei Kimura-Masuda,Hisashi Takei,Hiroshi Handa,Takuma Ishizaki,Takayuki Saitoh,Hiroaki Shimizu

doi:10.3390/cancers12020363

Nobuhiko Kobayashi, Norifumi Tsukamoto + Show 14 more

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https://doi.org/10.3390/cancers12020363

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Journal: Cancers	Publication Date: Feb 5, 2020
Citations: 14	License type: CC BY 4.0

Affiliation: Gunma University, Gunma University Hospital

Abstract

Acute myeloid leukemia (AML) with granulocytic sarcoma (GS) is characterized by poor prognosis; however, its underlying mechanism is unclear. Bone marrow samples from 64 AML patients (9 with GS and 55 without GS) together with AML cell lines PL21, THP1, HL60, Kasumi-1, and KG-1 were used to elucidate the pathology of AML with GS. RNA-Seq analyses were performed on samples from seven AML patients with or without GS. Gene set enrichment analyses revealed significantly upregulated candidates on the cell surface of the GS group. Expression of the adhesion integrin α7 (ITGA7) was significantly higher in the GS group, as seen by RT-qPCR (p = 0.00188) and immunohistochemistry of bone marrow formalin-fixed, paraffin-embedded (FFPE) specimens. Flow cytometry revealed enhanced proliferation of PL21 and THP1 cells containing surface ITGA7 in the presence of laminin 211 and stimulated ERK phosphorylation; this effect was abrogated following ITGA7 knockdown or ERK inhibition. Overall, high ITGA7 expression was associated with poor patient survival (p = 0.0477). In summary, ITGA7 is highly expressed in AML with GS, and its ligand (laminin 211) stimulates cell proliferation through ERK signaling. This is the first study demonstrating the role of integrin α7 and extracellular matrix interactions in AML cell proliferation and extramedullary disease development.

Highlights

Acute myelogenous leukemia (AML) is a hematopoietic malignancy, the prognosis of which remains poor despite intensive chemotherapy or allogeneic stem cell transplantation combined with advanced supportive care [1,2] The WHO classification, based primarily on genetic findings, has Cancers 2020, 12, 363; doi:10.3390/cancers12020363 www.mdpi.com/journal/cancersCancers 2020, 12, 363 replaced the previous FAB classification, and WHO treatment strategy and outcome prediction are broadly accepted [3,4]
To evaluate the differential expression of genes in acute myelogenous leukemia (AML) with or without granulocytic sarcoma (GS), we first performed comprehensive gene expression analysis of bone marrow specimens obtained from patients with AML
Based on the Gene set enrichment analysis (GSEA) data, we selected ITGA7 because the interaction between this integrin on leukemic cells and the ECM has not yet been studied but is speculated to play a role, especially in GS where leukemic cells are surrounded by a microenvironment different from the bone marrow (Figure 1b)

Summary

Introduction

Acute myelogenous leukemia (AML) is a hematopoietic malignancy, the prognosis of which remains poor despite intensive chemotherapy or allogeneic stem cell transplantation combined with advanced supportive care [1,2] The WHO classification, based primarily on genetic findings, has Cancers 2020, 12, 363; doi:10.3390/cancers12020363 www.mdpi.com/journal/cancersCancers 2020, 12, 363 replaced the previous FAB classification, and WHO treatment strategy and outcome prediction are broadly accepted [3,4]. Acute myelogenous leukemia (AML) is a hematopoietic malignancy, the prognosis of which remains poor despite intensive chemotherapy or allogeneic stem cell transplantation combined with advanced supportive care [1,2] The WHO classification, based primarily on genetic findings, has Cancers 2020, 12, 363; doi:10.3390/cancers12020363 www.mdpi.com/journal/cancers. Further predictors of prognosis are required to ensure an optimal treatment strategy for AML patients. We previously reported on the poor prognosis of AML with granulocytic sarcoma (GS) at diagnosis [5,6]. GS is an extramedullary disease, whereby leukemic cells form a mass outside the bone marrow and often emerge at the time of relapse and/or progression of AML, as well as at diagnosis [6]. Considering the prognostic value of GS, clarifying its underlying mechanism(s) may prove useful for identifying novel therapeutic targets as well as improving the prognosis

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