Page 13 - 2021_04-Haematologica-web

Editorials
New option for improving hematological recovery: suppression of luteinizing hormone
Harold K. Elias and Marcel R.M. van den Brink
Department of Immunology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA E-mail: MARCEL R.M. VAN DEN BRINK - vandenbm@mskcc.org
doi:10.3324/haematol.2020.274969
Current treatment modalities in leukemia are limit- ed by bone marrow (BM) toxicity, a common adverse effect of cytotoxic chemotherapy and transplant-related conditioning regimens, resulting in an increased risk of bleeding and infections. Strategies to protect the BM from cytotoxic injury could augment hematopoietic recovery and improve overall patient out- comes.
Hematopoietic recovery following cytotoxic therapies and irradiation is dependent on the maintenance of a rare population of hematopoietic stem cells (HSCs) - which have the ability to sustain long-term hematopoietic recovery.1,2 Following HSC transplant, there is evidence of decreased BM cellularity3 and diminished colony-forming capacity4-6 which could last up to approximately 5 years. Growing evidence attributes these functional defects to several intrinsic and extrinsic regulators which orches- trate radiation-induced senescent and pro-apoptotic pro- grams, thereby dictating HSC fate.7,8 Several radioprotec- tive agents have been identified,9 but very few mitigate
radiation toxicity in the post-injury setting. Historically, mouse studies have informed post-irradiation strategies to promote HSC regeneration which are either cytokine- based, such as a combination of stem cell factor, FMS-like tyrosine kinase 3 ligand, megakaryocyte growth and development factor (MGDF) and Interleukin-3 (IL-3),10 single agent IL-33,11 or inhibitors targeting PTPσ12 - none of which have been confirmed in the clinical setting. Cognate receptors for sex hormones and luteinizing hor- mone (LH)-releasing hormone (LHRH) have been identi- fied on HSC and implicated in their function.13-15 For example, LH can induce HSC expansion in vitro.13 Moreover, preclinical studies targeting the sex-steroid axis, have demonstrated enhanced hematopoietic stem cell function and immune recovery, following sex-steroid ablation16-18 and LHRH-antagonism.13
In this issue of Haematologica, Dalle and colleagues19 provide clinical evidence of BM recovery and long-term hematopoietic reconstitution following targeted therapy of the sex-steroid axis. They conducted a retrospective
Figure 1. Schematic model of luteinizing hormone-releasing hormone antagonism mediated cytoprotection which promotes hematopoietic stem cell recov- ery following haematopoietic injury. Dalle et al.19 provide clini- cal evidence for bone marrow recovery and long-term hematopoietic reconstitution with luteinizing hormone-releas- ing hormone (LHRH) antagonism (leuprolide) in leukemia patients following chemotherapy. HSC: hematopoietic stem cell; HSPC: hematopoietic stem and progen- itor cell; LHCGR: luteinizing hor- mone/choriogonadotropin receptor; LH: luteinizing. hor- mone. Figure created with BioRender.com.
haematologica | 2021; 106(4)
929