Inflammatory bone marrow microenvironment

May combine two claims.

S100A8 is responsible for the erythroid-differentiation defect: addition of recombinant S100A8 was sufficient to induce a differentiation defect in wild-type erythroid cells, and genetic inactivation of S100A8 expression rescued the erythroid-differentiation defect of Rps14-haploinsufficient HSCs.

“We demonstrated specifically that S100A8 is responsible for the erythroid-differentiation defect as addition of recombinant S100A8 was sufficient to induce a differentiation defect in wild-type erythroid cells, and genetic inactivation of S100A8 expression rescued the erythroid-differentiation defect of Rps14-haploinsufficient HSCs.”

• cites [70] Ribezzo, 2019, Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome, Leukemia sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Stromal (Gli1+) MSCs in MPN show altered expression of many HSC-regulatory genes and cytokines, including broad downregulation of HSC-retention factors, particularly CXCL12, in myelofibrosis, indicating transcriptional reprogramming from hematopoiesis support to inflammatory (profibrotic) programs.

“Also, our own data on the role of stromal (Gli11) MSCs in MPN showed altered expression of many HSC-regulatory genes and cytokines, including a broad downregulation of HSC-retention factors, in particular CXCL12, in myelofibrosis, indicating transcriptional reprogramming from hematopoiesis support to inflammatory (profibrotic) programs.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Erythroblastic islands are specialized niches supporting the proliferation and differentiation of erythroblasts, characterized by a central macrophage extending cytoplasmic protrusions to a ring of adjacent erythroblasts, and the interaction of cells within the island is crucial for early and late stages of erythroid maturation.

“Erythroblastic islands are very specialized niches supporting the proliferation and differentiation of erythroblasts.14 Erythroid islands are characterized by a central macrophage that extends cytoplasmic protrusions to a ring of adjacent erythroblasts.The interaction of cells within the island is crucial for early and late stages of erythroid maturation.”

• cites [14] Chasis, 2008, Erythroblastic islands: niches for erythropoiesis, Blood sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Perivascular mesenchymal cells that express CD146 in humans and Cxcl12-GFP, Nestin-GFP, full-length Leptin receptor, Prx-1-Cre, Osterix-Cre, and inducible Mx-1-Cre in mice generate osteoblastic cells and express factors that promote the maintenance of HSPCs.

“Although MSCs are a heterogeneous population and still require better characterization by surface markers, perivascular mesenchymal cells that express CD146 in humans and Cxcl12-green fluorescent protein, Nestin-green fluorescent protein, full-length Leptin receptor, Prx-1-Cre, Osterix-Cre, and inducible Mx-1-Cre in mice generate osteoblastic cells and express factors that promote the maintenance”

• cites [9] Morrison, 2014, The bone marrow niche for haematopoietic stem cells, Nature sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Other cell types that regulate HSC niches include osteoclasts, extracellular matrix, megakaryocytes, and calcium.

“Other cell types that regulate HSC niches include osteoclasts, extracellular matrix, megakaryocytes, and calcium.9”

• cites [9] Morrison, 2014, The bone marrow niche for haematopoietic stem cells, Nature sourceNot checked yet

  Not checked in the free run.

May combine two claims.

CXCL12 is essential in homing HSCs to the BM whereas KITL (SCF-1) supplies hematopoietic progenitors with an essential survival signal.

“CXCL12 is essential in homing HSCs to the BM whereas KITL (also known as stem cell factor 1 [SCF-1]) supplies hematopoietic progenitors with an essential survival signal.[10][11][12]”

• cites [10][11][12]Not checked yet

  Not checked in the free run.

May combine two claims.

Several stromal cell populations are involved in the regulation of hematopoiesis, and specific stromal cell populations regulate distinct hematopoietic progenitor populations.

“Several stromal cell populations are involved in the regulation of hematopoiesis, and recent studies have dissected and defined the role of specific stromal cell populations on regulating distinct hematopoietic progenitor populations.[3][4][5]”

• cites [3][4][5]Not checked yet

  Not checked in the free run.

May combine two claims.

Under normal conditions, HSCs are in a quiescent state; in response to inflammation, they rapidly start losing quiescence and transiently proliferate, also due to disturbed signals from their niche.

“Under normal conditions, HSCs are in a quiescent state.In response to inflammation, they rapidly start losing quiescence and transiently proliferate, also due to disturbed signals from their niche.”

May combine two claims.

Aging-associated intrinsic HSC alterations, including reduced self-renewal and myelopoiesis-skewed differentiation, strongly resemble functional changes of HSCs exposed to chronic inflammation, with increase of CD150 high HSCs giving rise to predominantly myeloid lineage cells.

“Aging-associated (intrinsic) HSC alterations, including reduced self-renewal and myelopoiesis-skewed differentiation, strongly resemble the functional changes of HSCs exposed to chronic inflammation: increase of CD150 high HSCs giving rise to predominantly myeloid lineage cells (myeloid skewing).”

May combine two claims.

TNF-a induces activation of caspases in erythroid precursor cells; subsequent cleavage and depletion of GATA-1 boosts PU.1-mediated skewing.

“In concert, another prominent inflammatory cytokine, TNF-a, induces activation of caspases in erythroid precursor cells.The subsequent cleavage and depletion of GATA-1 as vital transcription factor for the erythroid lineage boosts the PU.1-mediated skewing.29,30”

• cites [29] Back, 2004, PU.1 determines the self-renewal capacity of erythroid progenitor cells, Blood sourceNot checked yet

  Not checked in the free run.

• cites [30] Felli, 2005, Multiple members of the TNF superfamily contribute to IFN-γ-mediated inhibition of erythropoiesis, J Immunol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Aging not only causes intrinsic changes in HSCs but also induces significant changes in the BM microenvironment, leading to extrinsic mechanisms in HSC regulation.

“Thus, aging not only causes intrinsic changes in HSCs, but also induces significant changes in the BM microenvironment (leading to extrinsic mechanisms in HSC regulation).”

May combine two claims.

Inflammation in the natural aging process is reflected by anemia, immunosenescence, and thrombocytosis.

“Inflammation in the natural aging process is reflected by anemia, immunosenescence, and thrombocytosis.”

May combine two claims.

It is very likely that MSCs in both the endosteal and perivascular niche acquire inflammatory programs and directly affect the maturation of neighboring HSPCs.

“Thus, it is very likely that MSCs in both the endosteal and perivascular niche also acquire inflammatory programs and directly affect the maturation of neighboring HSPCs.”

May combine two claims.

Inflammatory signals induce lineage specification by different mechanisms in HSCs and impair HSC self-renewal.

“Furthermore, inflammatory signals induce lineage specification by different mechanisms in HSCs and impairs HSC self-renewal.”

May combine two claims.

MSCs and endothelial cells express various cytokine/chemokine receptors and PRRs and sense an inflammatory milieu due to hematopoietic challenges.

“Although spatial effects of inflammation in MSCs from different niches (endosteal and perivascular) have not been dissected specifically as compared with the interplay between the central macrophage and erythroid progenitor cells in the erythroid island, it has become increasingly clear that MSCs and endothelial cells (ECs) express various cytokine/chemokine receptors and PRRs.They sense an”

May combine two claims.

Inflammation affects the cellular functions of MSCs and ECs and influences hematopoiesis mainly through cytokine secretion or reaction to cytokines.

“These studies suggest that inflammation affects the cellular functions of MSCs and ECs, and influences hematopoiesis mainly through cytokine secretion or reaction to cytokines.[39][40][41]”

• cites [39][40][41]Not checked yet

  Not checked in the free run.

May combine two claims.

Through differentiation into mature adipocytes, multipotent MSCs lose their capacity to produce hematopoiesis-supporting factors such as CXCL-12, IGF-1, and Kitl, and the concentration of these is inversely correlated with the amount of BM fat.

“Through differentiation into mature adipocytes, multipotent MSCs lose their capacity to produce hematopoiesis supporting factors such as CXCL-12, IGF-1, and Kitl.The concentration of these is inversely correlated with the amount of BM fat.50”

• cites [50] Tuljapurkar, 2011, Changes in human bone marrow fat content associated with changes in hematopoietic stem cell numbers and cytokine levels with aging, J Anat sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In response to TLR4 activation, G-CSF is predominantly produced in ECs and strongly stimulates emergency granulopoiesis with recruitment of neutrophils to the site of infection.

“In response to TLR4 activation, G-CSF is predominantly produced in ECs, and strongly stimulates emergency granulopoiesis with recruitment of neutrophils to the site of infection.38”

• cites [38] Manz, 2014, Emergency granulopoiesis, Nat Rev Immunol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Myeloid cells and adipocytes produce numerous proinflammatory cytokines leading to a vicious cycle with accumulation of myeloid or myeloid-skewed cells in the BM.

“Myeloid cells and adipocytes further produce numerous proinflammatory cytokines leading to a vicious cycle with accumulation of myeloid or myelodid-skewed cells in the BM.48”

• cites [48] Biasco, 2016, In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases, Cell Stem Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

IFN-g can directly affect HSCs: STAT1 signaling leads to cycling and differentiation, ultimately resulting in stem cell exhaustion, whereas upregulation of SOCS1 blocks self-renewing capacities.

“IFN-g can directly affect HSCs: STAT1 signaling leads to cycling and differentiation, ultimately resulting in stem cell exhaustion, whereas upregulation of SOCS1 blocks the self-renewing capacities.56”

• cites [56] Chen, 2015, IFN-γ-mediated hematopoietic cell destruction in murine models of immune-mediated bone marrow failure, Blood sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Adipocytes secrete mediators suppressing hematopoiesis and upholding a proinflammatory environment such as TNF-a.

“Moreover, adipocytes have been described to secrete mediators suppressing hematopoiesis and upholding a proinflammatory environment such as TNF-a.51”

• cites [51] Naveiras, 2009, Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment, Nature sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The inflammatory microenvironment in the old BM cavity drives remodeling of the niche and hematopoiesis, and blocking proinflammatory cytokines is instrumental in reverting aging of the BM niche and impaired regenerative potential of old HSCs.

“This study proposed that the inflammatory microenvironment in the old BM cavity drives remodeling of the niche and hematopoiesis.They proposed that blocking of proinflammatory cytokines is instrumental in reverting the aging of the BM niche and the impaired regenerative potential of old HSCs.”

• cites [47] Verovskaya, 2018, Inflammatory changes in the bone marrow microenvironment drive both niche and blood system remodeling during aging, Exp Hematol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Quiescence prevents HSC depletion during chronic inflammation, indicating that multipotent progenitor (MPP) cells compensate the ongoing need, minimizing the necessity for HSCs to proliferate.

“Quiescence prevents HSC depletion during chronic inflammation.This indicates that multipotent progenitor (MPP) cells, responsible for daily blood maintenance, compensate the ongoing need, thereby minimizing the necessity for HSCs to proliferate.25”

• cites [25] Pietras, 2017, Inflammation: a key regulator of hematopoietic stem cell fate in health and disease, Blood sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Inflammation, particularly with IL-6 as a central mediator, affects iron metabolism, thereby affecting hemoglobin synthesis and causing anemia.

“Inflammation, in particular with IL-6 as a central mediator, affects iron metabolism, thereby affecting hemoglobin synthesis and, hence, anemia.27”

• cites [27] Macciò, 2005, Hemoglobin levels correlate with interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role of inflammation in cancer-related anemia, Blood sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Upregulation of TNF family member proteins in nursing macrophages and maturing erythroblasts inhibits their differentiation and induces extrinsic apoptosis.

“Additionally, upregulation of TNF family member proteins in nursing macrophages as well as maturing erythroblasts inhibits their differentiation even further and induces extrinsic apoptosis.31”

• cites [31] Koury, 2015, Anaemia in kidney disease: harnessing hypoxia responses for therapy, Nat Rev Nephrol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Recent evidence suggests that altered transcriptional landscapes, abnormal transduction of signaling cascades, epigenetic modifications, cytoskeletal polarity, cellular senescence, and clonal selection are key features of the aging process.

“Recent evidence suggests that altered transcriptional landscapes, abnormal transduction of signaling cascades, epigenetic modifications, cytoskeletal polarity, cellular senescence, and clonal selection are key features of the aging process.”

May combine two claims.

Recent single-cell studies on niche cells in young and aged mice demonstrated activation of inflammatory response programs, changes in osteoblastic differentiation, and metabolism with age, particularly through upregulation of IL1a/b.

“Recent single-cell studies on niche cells in young and aged mice demonstrated activation of inflammatory response programs, changes in osteoblastic differentiation, and also metabolism with age, in particular through upregulation of IL1a/b.47”

• cites [47] Verovskaya, 2018, Inflammatory changes in the bone marrow microenvironment drive both niche and blood system remodeling during aging, Exp Hematol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Under inflammatory conditions, the central macrophage can become a source of inflammatory mediators; IFN-g secreted by the central macrophage downregulates the Epo receptor on erythroid precursors while upregulating PU.1.

“Interestingly, under inflammatory conditions, the central macrophage itself can become a source of inflammatory mediators.IFN-g, secreted by the central macrophage, downregulates the Epo receptor on erythroid precursors, while at the same time upregulating PU.1.”

May combine two claims.

G-CSF, upregulated in infection, can enhance myelopoiesis through MSCs and suppress the production of CXCL12 from MSCs in the BM.

“Granulocyte colony-stimulating factor (G-CSF), as a myeloid-supporting cytokine that is upregulated in infection, can enhance myelopoiesis through MSCs and suppress the production of CXCL12 from MSCs in the BM.34”

• cites [34] Keating, 2012, Mesenchymal stromal cells: new directions, Cell Stem Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Both senescence/aging and other dysfunctions of the BM niche caused by chronic disease, infection, or aging may lead to overproduction of inflammatory signals that affect HSPCs and alter the fitness of their regulation microenvironment, which might lead to a microenvironment supporting transformed clones and not normal hematopoiesis, leading to a vicious cycle that further promotes expansion of a

“In summary, both senescence/ aging and other dysfunctions of the BM niche caused by chronic disease, infection, or aging may lead to overproduction of inflammatory signals that affect HSPCs and alter the fitness of their regulation microenvironment, which might lead to a microenvironment supporting transformed clones and not normal hematopoiesis, leading to a vicious cycle that further promotes”

May combine two claims.

A type 1 T-helper (Th1) cell-skewed response of the adaptive immune system is a major effector of damage and the major source of IFN-g, accompanied by a reduction in regulatory T cells (Tregs) in the marrow.

“Another major effector of damage is a type 1 T-helper (Th1) cell-skewed response of the adaptive immune system, which was also identified as the major source of IFN-g, accompanied by a reduction in regulatory T cells (Tregs) in the marrow.60”

• cites [60] Solomou, 2007, Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia, Blood sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Intrinsic defects of MDS hematopoietic cells directly alter the surrounding microenvironment, which in turn negatively affects hematopoiesis as an extrinsic mechanism.

“These data indicate that intrinsic defects of MDS hematopoietic cells directly alter the surrounding microenvironment, which in turn negatively affects hematopoiesis as an extrinsic mechanism.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Malignant cells use elaborate ways to shield themselves from immune response.

“Importantly, malignant cells use elaborate ways to shield themselves from immune response.”

May combine two claims.

Increased S100A8/S100A9 levels in the BM are linked to anemia and an increase in monocytes.

“Increased S100A8/S100A9 levels in the BM are linked to anemia and an increase in monocytes.”

May combine two claims.

A CD1-restricted T-cell response can lead to elimination of hematopoietic cells while creating a selective advantage for clones with deficiency for phosphatidylinositol glycan biosynthesis class A protein, reported in patients with paroxysmal nocturnal hemoglobinuria (PNH).

“A CD1-restricted T-cell response can lead to an elimination of hematopoietic cells, while at the same time creating a selective advantage for clones with deficiency for phosphatidylinositol glycan biosynthesis class A protein, reported in patients with paroxysmal nocturnal hemoglobinuria (PNH).63”

• cites [63] Gargiulo, 2013, Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria, Blood sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Increased IL-6 production or activation of TLR2 is critical for the development of the myeloproliferative phenotype of TET2-deficient hematopoietic cells.

“increased IL-6 production or activation of TLR2 is critical for the development of the myeloproliferative phenotype of TET2-deficient hematopoietic cells.”

• cites [85] Zhang, 2015, Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6, Nature sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

A 'reprogrammed' inflammatory microenvironment is a common theme in myeloid malignancies.

“A”

May combine two claims.

The microenvironment is massively 'reprogrammed' in myeloid malignancies and is inflammatory, leading to loss of function of the microenvironment.

“Thus, the conclusion can only be that the microenvironment is massively”

May combine two claims.

In murine models of MPN and AML, the hematological malignancy created neuropathic changes in the BM niche, which affected the activity of MSCs and altered the function of the HSC niche, leading to downregulated expression of many HSC-retention factors, including CXCL12 and SCF.

“In murine models of MPN 80 and AML, 81 the hematological malignancy created neuropathic changes in the BM niche, which affected the activity of MSCs and altered the function of the HSC niche, in particular leading to downregulated expression of many HSC-retention factors, including CXCL12 and SCF, indicating loss of hematopoiesis support.”

• cites [80] Arranz, 2014, Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms, Nature sourceNot checked yet

  Not checked in the free run.

• cites [81] Hanoun, 2014, Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche, Cell Stem Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Macrophages and monocytes are increased in chronic inflammatory states in aging and in myeloid malignancies and might be an important contributor to remodeling of the BM microenvironment in inflammation and hematopoietic disease.

“Macrophages and monocytes, as cells of the innate immune response, are increased in chronic inflammatory states in aging and in myeloid malignancies and might be an important contributor to the remodeling of the BM microenvironment in inflammation and hematopoietic disease (anemia, BM failure, and also leukemia).70”

• cites [70] Ribezzo, 2019, Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome, Leukemia sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Accumulation of inflammatory myelofibrotic cells and downregulation of factors regulating niche function and HSC retention, including CXCL12, n-cadherin, SCF, angiopoietin-1, and TGF-1 and -2, occur in this context.

“They demonstrated the accumulation of inflammatory myelofibrotic cells in this context and downregulation of factors regulating the niche function and HSC retention, including the chemokine CXCL12, n-cadherin, SCF, angiopoietin-1, and TGF-1 and -2.”

• cites [8] Schepers, 2013, Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche, Cell Stem Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

HSC attrition or leukemic transformation has been observed when inflammation is accompanied by cell-intrinsic DNA repair defects in HSCs or further fueled by dysregulated mechanisms in the BM microenvironment, particularly inflammation in niche cells.

“One hint might be that HSC attrition or leukemic transformation has been observed when inflammation is accompanied by cell-intrinsic DNA repair defects in HSCs or further fueled by dysregulated mechanisms in the BM microenvironment, in particular inflammation, particularly in niche cells.”

May combine two claims.

Raaijmakers and colleagues confirmed these results and additionally showed increased levels of S100A8 in the mesenchymal niche in MDS and Shwachman-Bodian-Diamond syndrome, which affects HSCs through excessive ROS production and genotoxic stress.

“Raaijmakers and colleagues confirmed these results and additionally showed increased levels of S100A8 in the mesenchymal niche in MDS and Shwachman-Bodian-Diamond syndrome, which affects HSCs through excessive reactive oxygen species (ROS) production and genotoxic stress.68,71”

• cites [68] Zambetti, 2016, Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia, Cell Stem Cell sourceNot checked yet

  Not checked in the free run.

• cites [71] Chen, 2016, Massive parallel RNA sequencing of highly purified mesenchymal elements in low-risk MDS reveals tissue-context-dependent activation of inflammatory programs, Leukemia sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The BM microenvironment is abnormal in myeloid malignancies and exhibits great similarities to an inflammatory state.

“In summary, we know that the BM microenvironment is abnormal in myeloid malignancies, and exhibits great similarities to an inflammatory state.”

May combine two claims.

MDSCs are sufficient to create an MDS phenotype in murine experiments, and targeting them or their expansion leads to reconstitution of normal hematopoiesis.

“MDSCs are sufficient to create an MDS phenotype in murine experiments, and targeting them or their expansion leads to reconstitution of normal hematopoiesis.76,77”

• cites [76] Chen, 2013, Induction of myelodysplasia by myeloid-derived suppressor cells, J Clin Invest sourceNot checked yet

  Not checked in the free run.

• cites [77] Eksioglu, 2017, Novel therapeutic approach to improve hematopoiesis in low risk MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 836858, Leukemia sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Adipocytes are increased in the aged BM and can release inflammatory signals.

“Adipocytes are increased in the aged BM and can also release inflammatory signals.”

Probably not a substantial claim: may not pass S4 (based).

Disease-related chronic inflammation and/or physiological aging leads to continuous production of proinflammatory signals systemically and locally in the BM.

“Disease-related chronic inflammation and/or physiological aging leads to the presence of continuous production of proinflammatory signals (systemically and locally in the BM).”

Probably not a substantial claim: may not pass S2 (checkable).

For other diseases defined by a less specific inflammatory BM microenvironment, intervention does not seem to be as straightforward.

“For other diseases, defined by a less specific inflammatory BM microenvironment, intervention does not seem to be as straightforward.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The central macrophage of the erythroblastic island can acquire an inflammatory phenotype and further contributes to inflammation in the BM microenvironment.

“The central macrophage of the erythroblastic island can also acquire an inflammatory phenotype and further contributes to inflammation in the BM microenvironment.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The mechanisms of immune evasion are as heterogeneous as AML itself and dependent on the differentiation stage of AML blasts.

“The mechanisms of immune evasion are as heterogeneous as AML itself and dependent on the differentiation stage of AML blasts.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Clonal hematopoiesis is observed with increasing frequency with age, but not all aging individuals develop hematologic malignancies or BM failure.

“although clonal hematopoiesis is observed with increasing frequency with age, not all aging individuals develop hematologic malignancies or BM failure.”

May combine two claims.

This leads to an inflammatory BM microenvironment as MSCs acquire an inflammatory secretory phenotype and release proinflammatory signals affecting the HSC niche and erythroblastic islands.

“In turn, this leads to an inflammatory BM microenvironment as MSCs of the BM, for example, nestin 1 (Nes 1 ), Gli1 1 , leptin-receptor (LepR 1 ) cells, acquire an inflammatory, secretory phenotype as well and also release proinflammatory signals that affect both the HSC niche and also the erythroblastic islands.”

May combine two claims.

Myeloid cells expand and innate immune cells/MDSCs are recruited.

“Myeloid cells expand and innate immune cells/MDSCs are recruited.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

High numbers of platelets are released by megakaryocytes whereas lymphoid cells decrease.

“High numbers of platelets are released by megakaryocytes whereas lymphoid cells decrease.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The reasons for not all aging individuals developing hematologic malignancies or BM failure are not clear, but likely involve interactions between cell-intrinsic and microenvironmental mechanisms as well as genetic/epigenetic factors.

“The reasons for this are not clear, but likely involve interactions between cell-intrinsic and microenvironmental mechanisms as well as the genetic/epigenetic”

May combine two claims.

Chronic inflammation can lead to decreased self-renewal of HSCs and skewed lineage output.

“and can lead to decreased self-renewal of HSCs and skewed lineage output.”

Probably not a substantial claim: may not pass S4 (based).

Inflammation in the BM microenvironment seems to be a common stress response to various stimuli.

“In summary, inflammation in the BM microenvironment seems to be a common stress response to various stimuli.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

There is a wide overlap between immune evasion strategies in AML and those observed in solid tumors.

“There is a wide overlap with evasion strategies observed in solid tumors.”

May combine two claims.

Blasts and malignant driver cells in MPNs upregulate B7-family proteins or programmed death-ligand 1 (PD-L1), inhibiting T cells through interaction with CTLA-4 and PD-1, respectively.

“Blasts and malignant driver cells in MPNs have also been described to upregulate B7-family proteins or programmed death-ligand 1 (PD-L1), inhibiting T cells through interaction with CTLA-4 and PD-1, respectively.[86][87][88]”

• cites [86][87][88]Not checked yet

  Not checked in the free run.

May combine two claims.

The erythroid system is very sensitive to inflammation and is affected in a majority of MDS cases.

“as the erythroid system in particular is very sensitive to inflammation and is in a majority of cases affected in MDSs.”

May combine two claims.

Inflammatory signaling in the microenvironment is deeply intertwined with the function of HSPCs and affects fate decisions.

“It becomes increasingly clear that inflammatory signaling in the microenvironment is deeply intertwined with the function of HSPCs and affecting fate decisions.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Aging-induced inflammation can be considered a physiological process, and it is not clear whether anti-inflammatory treatment without signs of malignancy or dysplasia in the BM would be beneficial.

“Although affecting hematopoiesis, aging-induced inflammation can be considered a physiological process and it is not clear whether anti-inflammatory treatment without any signs of malignancy of dysplasia in the BM were beneficial.”