Bone Marrow Microenvironment As a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Jan 8

PMID 36614005

Authors

Kathryn A Skelding

Daniel L Barry

Danielle Z Theron

Lisa F Lincz

Affiliations

Soon will be listed here.

Abstract

Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML. This review briefly discusses the role of the bone marrow microenvironment in AML development and progression, and as a source of novel therapeutic targets for AML. The main focus of this review is on drugs that modulate/target this bone marrow microenvironment and have been examined in in vivo models or clinically.

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References

Romano M, Petrella A, Bisogni R, Turco M, Venuta S . Effect of NF-kappaB/Rel inhibition on spontaneous vs chemotherapy-induced apoptosis in AML and normal cord blood CD34+ cells. Leukemia. 2003; 17(6):1190-2. DOI: 10.1038/sj.leu.2402953. View

Madlambayan G, Meacham A, Hosaka K, Mir S, Jorgensen M, Scott E . Leukemia regression by vascular disruption and antiangiogenic therapy. Blood. 2010; 116(9):1539-47. PMC: 2938842. DOI: 10.1182/blood-2009-06-230474. View

Cancilla D, Rettig M, Dipersio J . Targeting CXCR4 in AML and ALL. Front Oncol. 2020; 10:1672. PMC: 7499473. DOI: 10.3389/fonc.2020.01672. View

Benabbou N, Mirshahi P, Bordu C, Faussat A, Tang R, Therwath A . A subset of bone marrow stromal cells regulate ATP-binding cassette gene expression via insulin-like growth factor-I in a leukemia cell line. Int J Oncol. 2014; 45(4):1372-80. PMC: 4151812. DOI: 10.3892/ijo.2014.2569. View

Zhu J, Garrett R, Jung Y, Zhang Y, Kim N, Wang J . Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells. Blood. 2007; 109(9):3706-12. DOI: 10.1182/blood-2006-08-041384. View

Cho B, Zeng Z, Mu H, Wang Z, Konoplev S, McQueen T . Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy. Blood. 2015; 126(2):222-32. PMC: 4497963. DOI: 10.1182/blood-2015-02-628677. View

Boddu P, Borthakur G, Koneru M, Huang X, Naqvi K, Wierda W . Initial Report of a Phase I Study of LY2510924, Idarubicin, and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia. Front Oncol. 2018; 8:369. PMC: 6167965. DOI: 10.3389/fonc.2018.00369. View

Pinho S, Wei Q, Maryanovich M, Zhang D, Balandran J, Pierce H . VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells. Nat Cell Biol. 2022; 24(3):290-298. PMC: 8930732. DOI: 10.1038/s41556-022-00849-4. View

Winkler I, Barbier V, Wadley R, Zannettino A, Williams S, Levesque J . Positioning of bone marrow hematopoietic and stromal cells relative to blood flow in vivo: serially reconstituting hematopoietic stem cells reside in distinct nonperfused niches. Blood. 2010; 116(3):375-85. DOI: 10.1182/blood-2009-07-233437. View

10.

Vachhani P, Bose P, Rahmani M, Grant S . Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML. Physiol Genomics. 2014; 46(13):448-56. PMC: 4080281. DOI: 10.1152/physiolgenomics.00173.2013. View

11.

Ossenkoppele G, Stussi G, Maertens J, van Montfort K, Biemond B, Breems D . Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK). Blood. 2012; 120(24):4706-11. DOI: 10.1182/blood-2012-04-420596. View

12.

Walkley C, Olsen G, Dworkin S, Fabb S, Swann J, McArthur G . A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell. 2007; 129(6):1097-110. PMC: 1974882. DOI: 10.1016/j.cell.2007.05.014. View

13.

Jensen P, Mortensen B, Hodgkiss R, Iversen P, Christensen I, Helledie N . Increased cellular hypoxia and reduced proliferation of both normal and leukaemic cells during progression of acute myeloid leukaemia in rats. Cell Prolif. 2000; 33(6):381-95. PMC: 6496496. DOI: 10.1046/j.1365-2184.2000.00183.x. View

14.

Kiel M, Acar M, Radice G, Morrison S . Hematopoietic stem cells do not depend on N-cadherin to regulate their maintenance. Cell Stem Cell. 2009; 4(2):170-9. PMC: 2681089. DOI: 10.1016/j.stem.2008.10.005. View

15.

Curti A, Pandolfi S, Valzasina B, Aluigi M, Isidori A, Ferri E . Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood. 2006; 109(7):2871-7. DOI: 10.1182/blood-2006-07-036863. View

16.

Hwang H, Han A, Lee J, Park G, Min W, Kim H . Enhanced Anti-Leukemic Effects through Induction of Immunomodulating Microenvironment by Blocking CXCR4 and PD-L1 in an AML Mouse Model. Immunol Invest. 2018; 48(1):96-105. DOI: 10.1080/08820139.2018.1497057. View

17.

Maiti A, Konopleva M . How We Incorporate Venetoclax in Treatment Regimens for Acute Myeloid Leukemia. Cancer J. 2022; 28(1):2-13. PMC: 8785772. DOI: 10.1097/PPO.0000000000000567. View

18.

Karp J, Gojo I, Pili R, Gocke C, Greer J, Guo C . Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res. 2004; 10(11):3577-85. DOI: 10.1158/1078-0432.CCR-03-0627. View

19.

Jin L, Hope K, Zhai Q, Smadja-Joffe F, Dick J . Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006; 12(10):1167-74. DOI: 10.1038/nm1483. View

20.

Local A, Zhang H, Benbatoul K, Folger P, Sheng X, Tsai C . APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells. Mol Cancer Ther. 2018; 17(6):1177-1186. DOI: 10.1158/1535-7163.MCT-17-1209. View