The bone marrow stromal niche: a therapeutic target of hematological myeloid malignancies

ABSTRACT

Introduction: Myeloid malignancies are caused by uncontrolled proliferation of neoplastic cells and lack of mature hematopoietic cells. Beside intrinsic genetic and epigenetic alterations within the neoplastic population, abnormal function of the bone marrow stroma promotes the neoplastic process. To overcome the supportive action of the microenvironment, recent research focuses on the development of targeted therapies, inhibiting the interaction of malignant cells and niche cells.

Areas covered: This review covers regulatory networks and potential druggable pathways within the hematopoietic stem cell niche. Recent insights into the cell-to-cell interactions in the bone marrow microenvironment are presented. We performed literature searches using PubMed Database from 2000 to the present.

Expert opinion: Future therapy of myeloid malignancies must focus on targeted, personalized treatment addressing specific alterations within the malignant and the supporting niche cells. This includes treatments to overcome resistance mechanisms against chemotherapeutic agents mediated by supporting microenvironment. Novel techniques employing sequencing approaches, Crisp/Cas9, or transgenic mouse models are required to elucidate specific interactions between components of the bone marrow niche to identify new therapeutic targets.

KEYWORDS:

• Acute myeloid leukemia
• bone marrow microenvironment
• myelodysplastic syndrome
• myeloid malignancies
• myeloproliferative neoplasms
• niche

Article highlights

• Myeloid malignancies represent a highly heterogeneous group of diseases but share a similar origin in the hematopoietic stem and progenitor cell population

• Since therapeutic options are limited, there is an urgent need for new treatment strategies, to improve patient outcome

• The bone marrow microenvironment plays a crucial role for disease development and progression and represents a promising target for new treatments

• Diverse cell types and factors orchestrate the fate of proliferating and differentiating cells in the bone marrow and numerous signaling pathways were under clinical investigation for targeted therapy

• Beside ECs and MSCs, immunomodulatory therapies are a potent tool to treat various malignancies

• Since the ultimate treatment is still not discovered, modern techniques such as single-cell RNA-sequencing and high-resolution microscopy must provide more details about the niche to identify more druggable pathways to increase outcome for patients with myeloid malignancies

This box summarizes key points contained in the article.

Disclosure statement

No potential conflict of interest was reported by the authors.

Declarations of interest

W Fiedler has been on advisory boards of Amgen, Pfizer, Novartis, Jazz Pharmaceuticals, Ariad/Incyte, Abbvie, Celgene. He has received research funding from Amgen, support for meeting attendance from Amgen, Jazz Pharmaceuticals, Daiichi Sanchyo Oncology and Servier and support for medical writing services from Amgen, Pfizer, Böhringer and Abbvie. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper was not funded. The work of L Behrmann was supported in part by the Hamburger Krebsgesellschaft and Forschungsförderungsfonds der Medizinischen Fakultät UKE.