Summary of background knowledge of BMF diseases
| Disease . | Features . | Pathophysiology . |
|---|---|---|
| Acquired AA | Characterized by pancytopenia and BM hypocellularity, and results from cytotoxic T cell–mediated destruction of HSPCs1-13 | Type-1 cytokines, such as IFN-γ, can directly inhibit HSPC function, for example, by blocking hematopoietic growth factor signaling.14-21 |
| Of patients with SAA, ∼80% respond to immunosuppressive therapy alone or combined with eltrombopag3-6 | Regulatory T cells that suppress effector T cells are reduced in AA, and increase with IST.22,23 | |
| MDS | Originates from a stem cell, often mutated in ≥1 myeloid neoplasm genes | Like AA, abnormalities (involving cytotoxic T cells, TNF, interleukin-1, and others) have implicated immune effects in suppression of hematopoiesis.26-28 |
| Transformation to AML is common in higher-risk MDS | ||
| Most patients have lower-risk MDS, and pancytopenia (usually anemia) because of ineffective hematopoiesis is a common feature.29,30 | ||
| Approximately 20% of MDS is hypoplastic, resembling (and often confused with) AA in BM hypocellularity, and also in the specific cassette of frequently mutated genes, chromosome abnormalities, relatively favorable prognosis, and responsiveness to IST, as compared with classical cellular MDS.31,32 | ||
| T-LGLL | Lymphoproliferative disease that typically presents with cytopenia | Sequencing of the antigen-binding region (complementarity-determining region 3) and measurement of the variable β chain of the TCR by flow cytometry have defined clonality in LGL, but high-resolution profiling of the TCR repertoire in T-LGLL has been lacking because of limitations of the antibody panel, missing paired chain information, and heterogenous clones among individuals. |
| Characterized by clonal expansion of terminally differentiated effector-memory cytotoxic lymphocytes.33,34 | Using single-cell methods, it has been possible to generate a comprehensive landscape of T-cell clones, TCR-usage sharing among patients, clonality correlations with T-cell phenotypes, and evaluation of molecular mechanisms in responders to treatment. | |
| CHIP | Prevalent in older individuals and associated with increased risks of hematologic malignancies and all-cause mortality.35,36 | |
| Most common mutated genes in CHIP, DNMT3A, TET2, and ASXL1, are all epigenetic modifiers, and they are also frequently mutated in BMF syndromes such as AA and MDS.37-41 | ||
| VEXAS | Recently described severe adult autoinflammatory syndrome | Cytopenias and progressive BMF are common in VEXAS.42-44 |
| DBA | Rare congenital red blood cell hypoplastic disease featuring anemia, macrocytic erythrocytes, elevated erythrocyte adenosine deaminase activity, with short stature, physical abnormalities, and predisposition to cancer.45-47 | Most cases carry mutations in genes encoding the small 40S ribosomal protein subunit or the large 60S ribosome protein subunit. P53 activation resulted from abortive ribosome assembly and nucleolar stress have been implicated in pathogenesis.48-53 |
| GATA2 deficiency | Constitutional GATA2 deficiency has a broad spectrum of clinical phenotypes, including systemic infections, lymphedema, cytopenias, and myeloid neoplasm.54-58 | Constitutional GATA2 deficiency is caused by heterozygous germ line GATA2 mutations.54-58 |
| DADA2 | Monogenic vasculitis syndrome with clinical features including vasculitis and vasculopathy, recurrent cardiovascular accidents, systemic inflammation, immune deficiency, and hematologic abnormalities.59-62 | The disease phenotypes are caused by reduced ADA2 activity due to autosomal-recessive loss-of-function mutations in the ADA2 gene.59-62 |
| Telomere biology disorders | Complex set of constitutional syndromes defined by the presence of very short telomeres, with high risk of BMF, pulmonary fibrosis, and hepatic abnormalities.63 | Pathogenic germ line variants in genes involved in telomere maintenance (such as DKC1, TERC, TERT, NOP10, and NHP2) can lead to telomere erosion, and persistent DNA damage and stem cell decline.63 |
| Disease . | Features . | Pathophysiology . |
|---|---|---|
| Acquired AA | Characterized by pancytopenia and BM hypocellularity, and results from cytotoxic T cell–mediated destruction of HSPCs1-13 | Type-1 cytokines, such as IFN-γ, can directly inhibit HSPC function, for example, by blocking hematopoietic growth factor signaling.14-21 |
| Of patients with SAA, ∼80% respond to immunosuppressive therapy alone or combined with eltrombopag3-6 | Regulatory T cells that suppress effector T cells are reduced in AA, and increase with IST.22,23 | |
| MDS | Originates from a stem cell, often mutated in ≥1 myeloid neoplasm genes | Like AA, abnormalities (involving cytotoxic T cells, TNF, interleukin-1, and others) have implicated immune effects in suppression of hematopoiesis.26-28 |
| Transformation to AML is common in higher-risk MDS | ||
| Most patients have lower-risk MDS, and pancytopenia (usually anemia) because of ineffective hematopoiesis is a common feature.29,30 | ||
| Approximately 20% of MDS is hypoplastic, resembling (and often confused with) AA in BM hypocellularity, and also in the specific cassette of frequently mutated genes, chromosome abnormalities, relatively favorable prognosis, and responsiveness to IST, as compared with classical cellular MDS.31,32 | ||
| T-LGLL | Lymphoproliferative disease that typically presents with cytopenia | Sequencing of the antigen-binding region (complementarity-determining region 3) and measurement of the variable β chain of the TCR by flow cytometry have defined clonality in LGL, but high-resolution profiling of the TCR repertoire in T-LGLL has been lacking because of limitations of the antibody panel, missing paired chain information, and heterogenous clones among individuals. |
| Characterized by clonal expansion of terminally differentiated effector-memory cytotoxic lymphocytes.33,34 | Using single-cell methods, it has been possible to generate a comprehensive landscape of T-cell clones, TCR-usage sharing among patients, clonality correlations with T-cell phenotypes, and evaluation of molecular mechanisms in responders to treatment. | |
| CHIP | Prevalent in older individuals and associated with increased risks of hematologic malignancies and all-cause mortality.35,36 | |
| Most common mutated genes in CHIP, DNMT3A, TET2, and ASXL1, are all epigenetic modifiers, and they are also frequently mutated in BMF syndromes such as AA and MDS.37-41 | ||
| VEXAS | Recently described severe adult autoinflammatory syndrome | Cytopenias and progressive BMF are common in VEXAS.42-44 |
| DBA | Rare congenital red blood cell hypoplastic disease featuring anemia, macrocytic erythrocytes, elevated erythrocyte adenosine deaminase activity, with short stature, physical abnormalities, and predisposition to cancer.45-47 | Most cases carry mutations in genes encoding the small 40S ribosomal protein subunit or the large 60S ribosome protein subunit. P53 activation resulted from abortive ribosome assembly and nucleolar stress have been implicated in pathogenesis.48-53 |
| GATA2 deficiency | Constitutional GATA2 deficiency has a broad spectrum of clinical phenotypes, including systemic infections, lymphedema, cytopenias, and myeloid neoplasm.54-58 | Constitutional GATA2 deficiency is caused by heterozygous germ line GATA2 mutations.54-58 |
| DADA2 | Monogenic vasculitis syndrome with clinical features including vasculitis and vasculopathy, recurrent cardiovascular accidents, systemic inflammation, immune deficiency, and hematologic abnormalities.59-62 | The disease phenotypes are caused by reduced ADA2 activity due to autosomal-recessive loss-of-function mutations in the ADA2 gene.59-62 |
| Telomere biology disorders | Complex set of constitutional syndromes defined by the presence of very short telomeres, with high risk of BMF, pulmonary fibrosis, and hepatic abnormalities.63 | Pathogenic germ line variants in genes involved in telomere maintenance (such as DKC1, TERC, TERT, NOP10, and NHP2) can lead to telomere erosion, and persistent DNA damage and stem cell decline.63 |
DBA, Diamond-Blackfan anemia; IST, immunosuppressive therapy; T-LGLL, T-cell large granular lymphocyte leukemia.