Differentiation therapy for myeloid malignancies: beyond cytotoxicity

Abstract

Blocked cellular differentiation is a central pathologic feature of the myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Treatment regimens promoting differentiation have resulted in incredible cure rates in certain AML subtypes, such as acute promyelocytic leukemia. Over the past several years, we have seen many new therapies for MDS/AML enter clinical practice, including epigenetic therapies (e.g., 5-azacitidine), isocitrate dehydrogenase (IDH) inhibitors, fms-like kinase 3 (FLT3) inhibitors, and lenalidomide for deletion 5q (del5q) MDS. Despite not being developed with the intent of manipulating differentiation, induction of differentiation is a major mechanism by which several of these novel agents function. In this review, we examine the new therapeutic landscape for these diseases, focusing on the role of hematopoietic differentiation and the impact of inflammation and aging. We review how current therapies in MDS/AML promote differentiation as a part of their therapeutic effect, and the cellular mechanisms by which this occurs. We then outline potential novel avenues to achieve differentiation in the myeloid malignancies for therapeutic purposes. This emerging body of knowledge about the importance of relieving differentiation blockade with anti-neoplastic therapies is important to understand how current novel agents function and may open avenues to developing new treatments that explicitly target cellular differentiation. Moving beyond cytotoxic agents has the potential to open new and unexpected avenues in the treatment of myeloid malignancies, hopefully providing more efficacy with reduced toxicity.

Fig. 1. The role of inflammation in hematopoietic stem cell (HSC) differentiation—Inflammation and antigen stimulation have a number of downstream effects on HSC differentiation.

Extrinsic stimuli, such as interferon alpha (IFN-α) or lipopolysaccharide (LPS) have been shown to activate toll-like receptors (TLRs) 2, 4, and 9 on HSCs. This can result in secretion of vascular endothelial growth factor (VEGF), which increases endothelial permeability. It also results in intracellular activation of MYD88, leading to downstream activation of TRAF6 and NF-kB. Similarly, aging results in a decrease in miR-146a expression, which can also activate MYD88, TRAF6, and NF-kB. This activation results in autocrine and paracrine signaling through cytokines and chemokines, such as granulocyte colony stimulating factor (G-CSF), interleukin 6 (IL6), and tumor necrosis factor (TNF). In the acute state this results in stress granulopoiesis and terminal myeloid differentiation. Over time, prolonged signaling can result in myeloid skewing and a loss of HSC repopulation potential.

Fig. 2. The importance of megakaryocyte differentiation to lenalidomide action in del(5q) myelodysplastic syndrome – Myelodysplastic syndrome with del(5q) is characterized by a clonal malignant del(5q) hematopoietic stem cell (HSC), which is haploinsufficient for casein kinase 1A1 (CSNK1A1).

Lenalidomide binds cereblon (CRBN), which results in degradation of IKZF1 and derepression of RUNX1 and GATA2 activity, resulting in megakaryocytic differentiation. Lenalidomide binding to CRBN also promotes CSNK1A1 degradation which, in the context of haploinsufficiency, triggers megakaryocyte-selective cell death. Loss-of-function mutations in RUNX1, TP53 or GATA2 block lenalidomide-triggered megakaryocytic differentiation, and thereby apoptosis of the malignant clone.