MPN SCs co-opt physiological mechanisms of HSC sustenance
| Mechanism . | Related protein/pathway (molecular functions) . | In physiological HSC sustenance . | In MPN SC sustenance . | References . |
|---|---|---|---|---|
| Signal attenuation by negative regulators | SOCS2/3 (suppressor of JAK-STAT signaling) | SOCS2/3 promote HSC quiescence, and de-sensitize HSCs to cytokine stress | SOCS3 is upregulated in JAK2V617F-driven MPN SOCS2 is upregulated in advanced-stage CML (BP-CML) | 140-146 |
| DUSPs and PP2A (phosphatases that counteract with signaling kinases) | High DUSP1 in HSCs vs HPCs PP2A indirectly activates p38 MAPK, and the endogenous PP2A inhibitor FAM122A maintains HSC quiescence | DUSP1 is necessary for LSC survival in CML and PV Endogenous PP2A inhibitor SET and CIP2 are upregulated in advanced-stage CML Contradicting outcomes (positive and negative) of pharmacological inhibition of PP2A in CP-CML | 147-156 | |
| ERK signaling (counteracting with the procycling AKT signaling) | ERK signaling is necessary for HSC quiescence by suppressing AKT-mTOR signaling | Inhibition of ERK enhances the effect of ruxolitinib (JAK2 inhibitor) in JAK2V617F MPN Disrupting the JAK2V617F effector YBX1 suppressed the ERK effector MKNK1 and enhanced the effect of ruxolitinib in JAK2V617F MPN | 92,106,157-160 | |
| Insulation from activating cytokine signals | TGF-β (suppressing procycling cytokine stimulation, by reducing cytokine-mediated lipid raft clustering and signaling intensity) | TGF-β and its receptor/coreceptor (endoglin, CD105) are necessary for HSC maintenance | TGF-β promotes LSC survival in CML | 130-132,161-164 |
| MS4A3 (promoting common β chain [βc] cytokine [IL-3/GM-CSF] receptor signaling by escorting receptor endocytosis) | MS4A3 expression is low in HSCs and high in committed myeloid progenitors | LSCs suppress MS4A3 to prevent exhaustion in CML | 57,137,138 | |
| Lysosome pathway (lysosomal degradation of cytokine receptors reduces signaling intensity) | Endo-lysosomal pathway transcriptional factor TFEB is necessary for LT-HSC maintenance | 139 | ||
| Cell cycle arrest signals | TGF-β (upregulating CDK inhibitor p57) | p57 is highly enriched in mouse CD34− Kit+Lin−Sca1+ (KLS) cells vs cycling CD34+ KLS cells TGF-β neutralization delays HSC return to quiescence after mobilization | TGF-β promotes LSC survival in CML | 161,165,166 |
| GPI-anchored membrane proteins (mediates signaling of BM niche factor [such as TGF-β family protein, BMP4]) | Mutations in PIGA (enzyme for GPI-anchor synthesis) are associated with AA | 167-169 | ||
| Anti-inflammatory signaling | SLIT-ROBO (anti-inflammatory chemo-repellent factor and its receptor) | SLIT1 mutations and deletions are associated with AA | 170-177 | |
| Unknown | TNF-α mobilizes HSCs | JAK2V617F, BCR::ABL1 and TET2 loss confer resistance to TNF-α by MPN SCs | 5,178,179 | |
| Epigenetic regulation | DNMT3A (reversing DNA methylation and associated differentiation block) | Dnmt3a mutations are associated with expansion of quiescent HSC pool DNMT3A loss confers resistance to IFN-γ | 27 | |
| BCOR and BCORL1 (transcriptional corepressors that silence proliferation and differentiation genes) | Loss of BCOR and loss of BCORL1 are associated with AA | Mutations or aberrant expression of BCOR-suppressed genes (including TAL1, ETV6, and GATA2) occur in MPNs, suggesting their inactivation promotes MPN SC maintenance | 168,169,180-183 | |
| MECOM (EVI-1) (transcriptional repressor that maintains HSC quiescence and repopulating potential) | Mecom knockout increases differentiated myeloid cell output at the expense of primitive/quiescent HSCs MECOM loss-of-function mutations cause BMF | MECOM overexpression drives leukemogenesis MECOM negatively regulates MS4A3 in CML, consistent with its role for preserving the LSC pool | 77,138,184-191 |
| Mechanism . | Related protein/pathway (molecular functions) . | In physiological HSC sustenance . | In MPN SC sustenance . | References . |
|---|---|---|---|---|
| Signal attenuation by negative regulators | SOCS2/3 (suppressor of JAK-STAT signaling) | SOCS2/3 promote HSC quiescence, and de-sensitize HSCs to cytokine stress | SOCS3 is upregulated in JAK2V617F-driven MPN SOCS2 is upregulated in advanced-stage CML (BP-CML) | 140-146 |
| DUSPs and PP2A (phosphatases that counteract with signaling kinases) | High DUSP1 in HSCs vs HPCs PP2A indirectly activates p38 MAPK, and the endogenous PP2A inhibitor FAM122A maintains HSC quiescence | DUSP1 is necessary for LSC survival in CML and PV Endogenous PP2A inhibitor SET and CIP2 are upregulated in advanced-stage CML Contradicting outcomes (positive and negative) of pharmacological inhibition of PP2A in CP-CML | 147-156 | |
| ERK signaling (counteracting with the procycling AKT signaling) | ERK signaling is necessary for HSC quiescence by suppressing AKT-mTOR signaling | Inhibition of ERK enhances the effect of ruxolitinib (JAK2 inhibitor) in JAK2V617F MPN Disrupting the JAK2V617F effector YBX1 suppressed the ERK effector MKNK1 and enhanced the effect of ruxolitinib in JAK2V617F MPN | 92,106,157-160 | |
| Insulation from activating cytokine signals | TGF-β (suppressing procycling cytokine stimulation, by reducing cytokine-mediated lipid raft clustering and signaling intensity) | TGF-β and its receptor/coreceptor (endoglin, CD105) are necessary for HSC maintenance | TGF-β promotes LSC survival in CML | 130-132,161-164 |
| MS4A3 (promoting common β chain [βc] cytokine [IL-3/GM-CSF] receptor signaling by escorting receptor endocytosis) | MS4A3 expression is low in HSCs and high in committed myeloid progenitors | LSCs suppress MS4A3 to prevent exhaustion in CML | 57,137,138 | |
| Lysosome pathway (lysosomal degradation of cytokine receptors reduces signaling intensity) | Endo-lysosomal pathway transcriptional factor TFEB is necessary for LT-HSC maintenance | 139 | ||
| Cell cycle arrest signals | TGF-β (upregulating CDK inhibitor p57) | p57 is highly enriched in mouse CD34− Kit+Lin−Sca1+ (KLS) cells vs cycling CD34+ KLS cells TGF-β neutralization delays HSC return to quiescence after mobilization | TGF-β promotes LSC survival in CML | 161,165,166 |
| GPI-anchored membrane proteins (mediates signaling of BM niche factor [such as TGF-β family protein, BMP4]) | Mutations in PIGA (enzyme for GPI-anchor synthesis) are associated with AA | 167-169 | ||
| Anti-inflammatory signaling | SLIT-ROBO (anti-inflammatory chemo-repellent factor and its receptor) | SLIT1 mutations and deletions are associated with AA | 170-177 | |
| Unknown | TNF-α mobilizes HSCs | JAK2V617F, BCR::ABL1 and TET2 loss confer resistance to TNF-α by MPN SCs | 5,178,179 | |
| Epigenetic regulation | DNMT3A (reversing DNA methylation and associated differentiation block) | Dnmt3a mutations are associated with expansion of quiescent HSC pool DNMT3A loss confers resistance to IFN-γ | 27 | |
| BCOR and BCORL1 (transcriptional corepressors that silence proliferation and differentiation genes) | Loss of BCOR and loss of BCORL1 are associated with AA | Mutations or aberrant expression of BCOR-suppressed genes (including TAL1, ETV6, and GATA2) occur in MPNs, suggesting their inactivation promotes MPN SC maintenance | 168,169,180-183 | |
| MECOM (EVI-1) (transcriptional repressor that maintains HSC quiescence and repopulating potential) | Mecom knockout increases differentiated myeloid cell output at the expense of primitive/quiescent HSCs MECOM loss-of-function mutations cause BMF | MECOM overexpression drives leukemogenesis MECOM negatively regulates MS4A3 in CML, consistent with its role for preserving the LSC pool | 77,138,184-191 |
AA, aplastic anemia; CDK, cyclin dependent kinase; CP, chronic phase; ERK, extracellular signal-regulated kinase; GM-CSF, granulocyte-macrophage colony-stimulating factor.