Main niche alterations in different myeloid malignancies
| Disease name . | . | Alteration . |
|---|---|---|
| AML | Disease phenotype | Hyperproliferation and impaired differentiation of HSC and myeloid progenitors |
| Acute rapidly progressing disease | ||
| Genetic LSC alterations | Chromosomal translocations, inversions, mutations in NPM1, CEBPA, KIT, RUNX1, FLT-IDT, or epigenetic factors | |
| Niche alterations | Neuropathy correlating with altered microenvironment16 | |
| PTH activation in osteoblasts accelerates AML.4 | ||
| CD44 and E-selectin are important for LSC niche adhesion and maintaining LSC primitive state.94,95,99 | ||
| β-catenin activation in osteoblasts stimulates Jag1 expression which activates Notch signaling in HSCs to induce AML.113,114 | ||
| Ph– MPN | Disease phenotype | Clonal HSC disorder with hyperproliferation and expansion of myeloid cells |
| Erythrocythemia (PV), thrombocythemia (ET), BM fibrosis (PMF) | ||
| Slow progression, chronic disease stage, possible transformation to AML | ||
| Genetic LSC alterations | Mutations in JAK2 (PV, ET, PMF), MPL (ET, PMF), CALR (ET, PMF) | |
| Niche alterations | LSCs secrete IL-1β, which damages Schwann cells and sympathetic nerve terminals causing early neuropathy. This results in apoptosis of nestin+ BMSCs, reduces Cxcl12 production, and results in thrombocytosis and fibrosis.80 | |
| Reduced osteoblast numbers at late stage of the disease.112 | ||
| Inactivation of Notch or deletion of retinoic acid receptor γ or retinoblastoma protein can cause niche-induced MPN.5,6,8 | ||
| PTPN11 activation in BMSCs induces CCL3-mediated monocyte recruitment and subsequent IL-1β–dependent HSC hyperactivation driving MPN progression.79 | ||
| CML | Disease phenotype | Clonal HSC disorder with hyperproliferation and expansion of myeloid cells |
| Slow progression, chronic disease stage, possible transformation to AML | ||
| Genetic LSC alterations | Chromosomal translocation resulting in BCR-ABL gene fusion | |
| Niche alterations | CML cells support BMSC proliferation and abnormal differentiation of osteoblasts into inflammatory cells which secrete proinflammatory cytokines that trigger myeloid progenitor and osteoblast expansion as well as stromal remodeling. CXCL12 is reduced in BMSCs favoring LSCs at the expense of HSC expansion.81 | |
| TGF-β and Notch cause stromal remodeling.81 | ||
| PTH activation in osteoblasts attenuates CML.4 | ||
| CML cells instruct BMSCs to secrete PIGF, which stimulates angiogenesis, CML proliferation, and metabolism.81 | ||
| CD44/E-selectin-dependent adhesion of LSCs to niche cells93,98 | ||
| Osteoblast expansion negatively regulates HSC and LSC proliferation.111 | ||
| MDS | Disease phenotype | Differentiation defects in HSCs |
| Pancytopenia, myelodysplasia | ||
| Slow progression, chronic disease, possible transformation to AML | ||
| Genetic LSC alterations | Chromosomal deletions, NUP98-HOXD13 fusion, mutations in RUNX1, CEBPA, EVI1, NPM1, RAS and splice and methylation factors | |
| Niche alterations | Dicer deletion in osteoprogenitors causes MDS.76 | |
| Leukemic cells can reprogram BMSCs into BMSCs of a malignant niche, which provide the important niche factors LIF, VEGF, IGF-BP2 and N-cadherin.83 | ||
| Abnormal WNT signaling causes proliferation defects in BMSCs because of increased cell senescence.84-86 | ||
| Increased osteogenic potential of BMSCs110 | ||
| p53-S100A8/9-TLR inflammatory signaling in BMSCs causes genotoxic stress in HSCs and supports MDS development.78 |
| Disease name . | . | Alteration . |
|---|---|---|
| AML | Disease phenotype | Hyperproliferation and impaired differentiation of HSC and myeloid progenitors |
| Acute rapidly progressing disease | ||
| Genetic LSC alterations | Chromosomal translocations, inversions, mutations in NPM1, CEBPA, KIT, RUNX1, FLT-IDT, or epigenetic factors | |
| Niche alterations | Neuropathy correlating with altered microenvironment16 | |
| PTH activation in osteoblasts accelerates AML.4 | ||
| CD44 and E-selectin are important for LSC niche adhesion and maintaining LSC primitive state.94,95,99 | ||
| β-catenin activation in osteoblasts stimulates Jag1 expression which activates Notch signaling in HSCs to induce AML.113,114 | ||
| Ph– MPN | Disease phenotype | Clonal HSC disorder with hyperproliferation and expansion of myeloid cells |
| Erythrocythemia (PV), thrombocythemia (ET), BM fibrosis (PMF) | ||
| Slow progression, chronic disease stage, possible transformation to AML | ||
| Genetic LSC alterations | Mutations in JAK2 (PV, ET, PMF), MPL (ET, PMF), CALR (ET, PMF) | |
| Niche alterations | LSCs secrete IL-1β, which damages Schwann cells and sympathetic nerve terminals causing early neuropathy. This results in apoptosis of nestin+ BMSCs, reduces Cxcl12 production, and results in thrombocytosis and fibrosis.80 | |
| Reduced osteoblast numbers at late stage of the disease.112 | ||
| Inactivation of Notch or deletion of retinoic acid receptor γ or retinoblastoma protein can cause niche-induced MPN.5,6,8 | ||
| PTPN11 activation in BMSCs induces CCL3-mediated monocyte recruitment and subsequent IL-1β–dependent HSC hyperactivation driving MPN progression.79 | ||
| CML | Disease phenotype | Clonal HSC disorder with hyperproliferation and expansion of myeloid cells |
| Slow progression, chronic disease stage, possible transformation to AML | ||
| Genetic LSC alterations | Chromosomal translocation resulting in BCR-ABL gene fusion | |
| Niche alterations | CML cells support BMSC proliferation and abnormal differentiation of osteoblasts into inflammatory cells which secrete proinflammatory cytokines that trigger myeloid progenitor and osteoblast expansion as well as stromal remodeling. CXCL12 is reduced in BMSCs favoring LSCs at the expense of HSC expansion.81 | |
| TGF-β and Notch cause stromal remodeling.81 | ||
| PTH activation in osteoblasts attenuates CML.4 | ||
| CML cells instruct BMSCs to secrete PIGF, which stimulates angiogenesis, CML proliferation, and metabolism.81 | ||
| CD44/E-selectin-dependent adhesion of LSCs to niche cells93,98 | ||
| Osteoblast expansion negatively regulates HSC and LSC proliferation.111 | ||
| MDS | Disease phenotype | Differentiation defects in HSCs |
| Pancytopenia, myelodysplasia | ||
| Slow progression, chronic disease, possible transformation to AML | ||
| Genetic LSC alterations | Chromosomal deletions, NUP98-HOXD13 fusion, mutations in RUNX1, CEBPA, EVI1, NPM1, RAS and splice and methylation factors | |
| Niche alterations | Dicer deletion in osteoprogenitors causes MDS.76 | |
| Leukemic cells can reprogram BMSCs into BMSCs of a malignant niche, which provide the important niche factors LIF, VEGF, IGF-BP2 and N-cadherin.83 | ||
| Abnormal WNT signaling causes proliferation defects in BMSCs because of increased cell senescence.84-86 | ||
| Increased osteogenic potential of BMSCs110 | ||
| p53-S100A8/9-TLR inflammatory signaling in BMSCs causes genotoxic stress in HSCs and supports MDS development.78 |
PTH, parathyroid hormone; TLR, toll-like receptor.