Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration

Abstract

The transcription factor hepatic leukemia factor (HLF) is strongly expressed in hematopoietic stem cells (HSCs) and is thought to influence both HSC self-renewal and leukemogenesis. However, the physiological role of HLF in hematopoiesis and HSC function is unclear. Here, we report that mice lacking Hlf are viable with essentially normal hematopoietic parameters, including an intact HSC pool during steady-state hematopoiesis. In contrast, when challenged through transplantation, Hlf-deficient HSCs showed an impaired ability to reconstitute hematopoiesis and became gradually exhausted upon serial transplantation. Transcriptional profiling of Hlf-deficient HSCs revealed changes associated with enhanced cellular activation, and cell-cycle analysis demonstrated a significant reduction of quiescent HSCs. Accordingly, toxic insults targeting dividing cells completely eradicated the HSC pool in Hlf-deficient mice. In summary, our findings point to HLF as a critical regulator of HSC quiescence and as an essential factor for maintaining the HSC pool during regeneration.

Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates

“…Sim- plete loss of function in the PU.1/CEBPA/RUNX1 circuit, since experimentally, complete inactivation of PU.1, CEBPA, or RUNX1 kills AML cells, even as partial loss of function of any one of these is leukemogenic (17,43,(68)(69)(70)(71)(72); and accordingly, NPM1, RUNX1, and biallelic CEBPA mutations, though highly recurrent in AML, are mutually exclusive (37)(38)(39). PU.1, CEBPA, and RUNX1 have been shown to promote exponential replication kinetics by binding to MYC enhancers to produce high-grade activation of MYC (the master transcription factor coordinator of cell proliferation) and by co-binding with MYC at its target genes (73)(74)(75)(76)(77)(78)(79)(80)(81)(82). This contrasts with the quiescence imposed by stem cell master transcription factors such as HLF in HSCs (73)(74)(75)(76)(77)(78)(79)(80)(81)(82).…”

“…PU.1, CEBPA, and RUNX1 have been shown to promote exponential replication kinetics by binding to MYC enhancers to produce high-grade activation of MYC (the master transcription factor coordinator of cell proliferation) and by co-binding with MYC at its target genes (73)(74)(75)(76)(77)(78)(79)(80)(81)(82). This contrasts with the quiescence imposed by stem cell master transcription factors such as HLF in HSCs (73)(74)(75)(76)(77)(78)(79)(80)(81)(82). In computational analyses, such skewing of intrinsic replication rates logarithmically favors decoupling replication from forward differentiation in lineage progenitors as the most efficient strategy for malignant transformation (83).…”

Guiding T lymphopoiesis from pluripotent stem cells by defined transcription factors

“…To identify these absent factors, we sorted the single iHEC from iRunx1 -ESC and performed single-cell RNA-Seq. In comparison with E11 T1-pre-HSC (CD31 + CD41 low CD45 − c-kit + CD201 high ), we identified eight hematopoietic-essential transcription factors, Hoxa5 8 , Hoxa7 27 , Hoxa9 28 , Hoxa10 29 , Hlf 30 , Ikzf1 31 , Nkx2-3 32 , and Setbp1 33 , which were barely expressed in iRunx1 -ES-derived iHEC but abundantly expressed in E11 T1-pre-HSC (Fig. 1b).…”

Junctional Adhesion Molecule 2 Represents a Subset of Hematopoietic Stem Cells with Enhanced Potential for T Lymphopoiesis

“…When the plates were coated with a 10 times lower concentration of Fc-DLL4 ( lo DLL4), the elevation of Notch/Delta genes was abrogated. However, cocoating of the lo DLL4 plates with recombinant Fc-Jam1 enabled the induction of Notch/Delta related genes (e.g., Ccr7) at similar levels to hiDLL4 coating, as well as a critical HSC regulator Hlf ( Figure 3D; Komorowska et al, 2017). These effects were not observed in Jam2 low HSCs ( Figure 3D), suggesting that Jam2 high HSCs have an advantage in transduction of Notch/Delta signals.…”