LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance

Abstract

Key Points• Notch1/DII4-mediated signals are normally suppressed by LRF, preventing HSCs from premature T-cell differentiation in the bone marrow.• Erythroblastic islands may have the capacity to regulate the fate and function of HSCs. IntroductionFor life-long hematopoiesis, most immature hematopoietic stem cells (HSCs), so-called long-term HSCs (LT-HSCs), remain dormant, but in response to hematopoietic stress, they actively cycle to generate multi-lineage blood cells without depleting the HSC pool. 1 These fate decisions are governed by intrinsic and extrinsic mechanisms. Relevant to extrinsic regulation, adult HSCs reside in a specialized microenvironment within the bone marrow (BM), the "niche," which is composed of multiple types of supporting cells that express membrane-bound and secreted factors. 2,3 Osteoblasts, endothelial cells, perivascular cells, mesenchymal stem cells, and glial cells have been proposed as components of the BM microenvironment. 3 These studies reveal how both self-renewal and quiescence of adult HSCs are maintained; however, how the balance between self-renewal and differentiation is regulated in the niche remains largely unknown.The highly conserved Notch signaling pathway regulates many cell-fate decisions and homeostasis in various organs. 4 In humans its dysregulation is associated with many types of cancer and inherited congenital anomalies. 4 There are 4 mammalian homologs of the Notch receptor (Notch 1-4) and 5 ligands: Delta-like-1, 3 and 4, which belong to the Delta ligand family, and Jagged-1 and 2, which belong to the Serrate family. 5 After ligand engagement, the intracellular domain of the Notch receptor (ICN) undergoes multiple proteolytic cleavages and translocates to the nucleus, where it binds the recombination signal-binding protein 1 for j (RBP-j, also known as CSL/CBF1) and mastermind-like coactivators (MAML1-3), and activates downstream targets, such as hairy and enhancer of split homologue-1 (Hes-1). 5 Notch is indispensable for the emergence of embryonic hematopoiesis 6 ; however, its role in adult HSC function is controversial. In addition, it is not completely understood at which HSC/progenitor stages Notch receptors are expressed and which Notch ligands are expressed in the BM microenvironment.LRF (for leukemia/lymphoma related factor), also known as Pokemon, ZBTB7a, FBI-1, and OCZF, is a POZ and Krüppel (POK)-type transcription factor with multiple functions in hematopoietic development, oncogenesis, and humoral immunity. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From inhibitors, which block Notch signaling, rescues aberrant lymphoid development, suggesting that Lrf antagonizes the Notch pathway at the HSC/progenitor level. 8 Furthermore, despite its cr...

Role of LRF/Pokemon in lineage fate decisions

“…35 Furthermore, a slight but significant reduction in the numbers of granulocytemacrophage progenitors was observed in Lrf 2/2 fetal liver and in Lrf Flox/Flox ;Mx1-Cre bone marrow. 31 It remains to be clarified whether Lrf intrinsically functions during myeloid development in a developmental stage-specific manner or does so in a non-cellautonomous fashion (eg, niche effects).…”

“…Accordingly, The role of Notch in adult HSC homeostasis remains highly controversial, as detailed in recent reviews. [51][52][53][54] The study by Lee et al 35 demonstrates that Notch1/Dll4-mediated signals are normally suppressed by LRF in the bone marrow, preventing HSCs from premature T-cell differentiation.…”

“…In a recent manuscript published in Blood, 35 Maeda's group provided the first evidence that differentiated hematopoietic cells, the progeny of HSCs, have the capacity to in turn regulate the fate and function of their parents (ie, undifferentiated HSCs) in a hematopoietic cell-autonomous but not HSC-autonomous circuit ( Figure 5). In this study, Lrf ( Figure 5).…”

“…Furthermore, in vivo anti-Dll4 treatment restored HSC numbers in Lrf Flox/Flox ;Mx1-Cre mice. 35 These results prompted the authors to investigate the erythroblasts in the bone marrow as a potential source of the non-cell-autonomous T-cell instructive signal responsible for the LT-HSCs phenotype.…”

Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas

“…ThPOK belongs to the POK family of transcription factors, which includes other factors that mediate important roles in hematopoiesis, i.e., Bcl6, PLZF, and LRF (7)(8)(9)(10)(11)(12). Disregulated expression of POK factors is associated with various hematological malignancies, including PLZF in AML (13), Bcl6 in B-cell lymphoma (14,15), and LRF/Pokemon in T-cell lymphoma and lung cancer (16).…”