RNAi screen identifies MAPK14 as a druggable suppressor of human hematopoietic stem cell expansion

Abstract

We report on a forward RNAi screen in primary human hematopoietic stem and progenitor cells, using pooled lentiviral shRNA libraries deconvoluted by next generation sequencing. We identify

Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells

“…As recently reported, the inactivation of p38 activity by small molecule inhibitors maintained stemness ex vivo in human and murine HSCs (Baudet et al, 2012;Zou et al, 2012). Furthermore, an increase in reactive oxygen species results in the activation of p38 and finally in HSC …”

p38α Activates Purine Metabolism to Initiate Hematopoietic Stem/Progenitor Cell Cycling in Response to Stress

“…Treatment with the antioxidant N-acetyl-L-cysteine (NAC) or a p38MAPK inhibitor rescues HSPC number and function in serial BMT or Atm À/À cells in mice (Ito et al, 2004;Ito et al, 2006). Also, Mapk14 knockdown or p38MAPK inhibition promotes proper cell-cycle progression following BMT or in exvivo-expanded HSPCs (Baudet et al, 2012;Zou et al, 2012). Thus, p38MAPK inhibition is thought to suppress aberrant HSPC proliferation and protect HSPCs from exhaustion or replicative senescence in stress settings or in the context of damage associated with aging (Geiger et al, 2013;Rossi et al, 2008).…”

“…Aberrant ROS levels in HSPCs during BMT or following loss of the kinase ataxia-telangiectasia-mutated (ATM) reportedly activate the p38MAPK/p16 INK4a /Rb axis, resulting in HSPC defects, such as replicative senescence (Baudet et al, 2012;Ito et al, 2006). Treatment with the antioxidant N-acetyl-L-cysteine (NAC) or a p38MAPK inhibitor rescues HSPC number and function in serial BMT or Atm À/À cells in mice (Ito et al, 2004;Ito et al, 2006).…”

Identification of the chemokine CCL28 as a growth and survival factor for human hematopoietic stem and progenitor cells

“…9,22 Thus, the further assessment of CCL28 to improve ex vivo culture conditions for HSPCs should be conducted in a systematic manner with other growth factor contexts and/or recently discovered molecules for HSC expansion. [3][4][5][6]10,23 Finally, given the presence of CCL28 in the BM microenvironment 24 (supplemental Figure 7), the potential role of CCL28 in regulating HSPCs in vivo as a niche-secreted factor under both normal and malignant 25 conditions represents another interesting topic for future studies. …”