Activity of a Heptad of Transcription Factors Is Associated with Stem Cell Programs and Clinical Outcome in Acute Myeloid Leukaemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3525-3525
Author(s):  
Eva Diffner ◽  
Dominik Beck ◽  
Emma Gudgin ◽  
Julie Thoms ◽  
Kathy Knezevic ◽  
...  
Keyword(s):  
Risk Factor ◽  
Stem Cell ◽  
Transcription Factors ◽  
Clinical Outcome ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Leukemic Cells ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 3525 Leukaemic transformation is driven by aberrant transcriptional programs often in combination with abnormal proliferative signalling. These programs operate in normal hematopoiesis where they are involved in hematopoietic stem cell (HSC) proliferation and maintenance. ERG is a component of normal and leukemic stem cell signatures and high ERG expression has been proposed as a risk factor for poor prognosis in acute myeloid leukemia (AML). However, mechanisms that underlie ERG expression in AML and how its expression relates to leukemic stemness are unknown. We report that ERG expression in AML is associated with activity of the ERG+85 stem cell enhancer (SCE) and a heptad of transcription factors that combinatorially regulate genes in normal HSCs. Gene expression signatures derived from ERG+85 stem cell enhancer (Fig A) and heptad activity (Fig B) predict clinical outcome in a cytogenetically normal cohort of AML (CN-AML) patients when ERG expression alone fails. The heptad signature is an independent risk factor for poor overall and event-free survival (Fig C). There were no long-term survivors amongst patients with a heptad signature, FLT3 mutations and wild-type NPM1 (Fig D) pointing to a hitherto unappreciated link between aberrant signaling and transcriptional mediators of hematopoietic stem cell identity. In two independent cohorts, the heptad signature was as closely associated with wild-type NPM1 AML as the HOX signature was with mutant NPM1 AML (Fig E–F) suggestive of a collective role for these transcription factors in mediating the leukemic signature in the former. Taken together, these results show that key transcriptional regulators cooperate in establishing stem cell signatures in leukemic cells and that the underlying spectrum of somatic mutations contributes to the development of these signatures and modulate their influence on clinical outcome. Disclosures: No relevant conflicts of interest to declare.

A Novel MBT-Containing Protein, Hemp, Plays Essential Roles In Skeletal Formation and Hematopoietic Stem Cell Function.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1597-1597
Author(s):  
Phyo Wai Htun ◽  
Keiyo Takubo ◽  
Hideaki Oda ◽  
Feng Ma ◽  
Kenjiro Kosaki ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Function ◽  
Conflicts Of Interest ◽  
Conditional Knockout ◽  
Thoracic Vertebrae ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Epigenetic Regulator ◽  
Skeletal Formation

Abstract Abstract 1597 Hemp (hematopoietic expressed mammalian polycomb, also denoted as mbt-containing 1) gene was originally identified in the hematopoietic stem cell (HSC)-enriched fraction of the mouse fetal liver (FL). It encodes a protein containing a putative Cys2-Cys2 zinc-finger region, followed by four tandem malignant brain tumor (MBT) repeats, which is frequently observed in polycomb gene (PcG) proteins. The structural characteristics strongly suggest that Hemp functions as an epigenetic regulator, but its biological role remains unknown. To address this issue, we generated hemp-deficient (hemp–/–) mice. Hemp–/– mice died soon after birth. Although no abnormalities were detected in internal organs, skeletal analysis exhibited a variety of malformations. Severe deformities were observed in the thoracic cavity, strongly suggesting that hemp–/– mice died of respiratory failure. Interestingly, they showed malformations of cervical and thoracic vertebrae, which were different from typical homeotic transformations observed in PcG-deficient mice. These results suggest that Hemp governs downstream target genes in distinct manners from conventional PcG proteins. The hematopoietic analysis of hemp in the FL showed that hemp is preferentially expressed in CD150+LSK and CD150–LSK HSC fractions in the hematopoietic hierarchy. Hemp–/– FL contained a significantly reduced number of hematopoietic cells and produced fewer number of hematopoietic colonies as compared to hemp+/+ FL. The decreases correlated with reduced number of CD150+LSK HSCs in hemp–/– FL, which generated much fewer hematopoietic colonies in the HPP-CFC assay. In addition, the competitive repopulation assay exhibited that the hematopoietic reconstitution ability of hemp–/– FL CD150+LSK HSCs was significantly impaired. Moreover, microarray analysis revealed that expression levels of several genes, such as Prdm16, Sox4, and Erdr1 were altered in hemp–/– FL HSCs. Since hemp–/– mice died at neonate, the role of Hemp in adult hematopoiesis remains to be elucidated. To address this issue, we generated hemp conditional knockout (cKO) mice. Acquired deletion of Hemp in the hematopoietic tissues was successfully achieved by crossing hempflox/flox mice with MxCre mice and stimulating the compound mice with pIpC. Analysis of the hematopoietic tissues revealed that the cell numbers of Mac+Gr1– and Mac+Gr1+ fractions in the hemp cKO bone marrow (BM) were significantly increased and decreased, respectively, as compared to those of the wild-type BM. However, no apparent differences have so far been observed between hemp cKO and wild-type littermates in functional analyses, such as colony forming activity and competitive repopulation ability of the BM cells. Here, we report that a novel MBT-containing protein, Hemp, plays essential roles in skeletal formation and HSC function during embryogenesis and also contributes to myeloid differentiation in adult hematopoiesis. Since Hemp likely functions as an epigenetic regulator, further studies will be required to clarify whether and what methylated lysine residues Hemp interacts with through the MBT repeats, what kind of genes are direct targets of Hemp, and how Hemp exerts its biological activity. Disclosures: No relevant conflicts of interest to declare.

Toll like Receptor 2 Signaling Regulates Hematopoietic Stem Cell Function and Promotes G-CSF Mediated HSC Mobilization

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4334-4334
Author(s):  
Angela Herman ◽  
Molly Romine ◽  
Darlene Monlish ◽  
Laura G. Schuettpelz
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Immune Cell ◽  
Conflicts Of Interest ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Tlr2 Signaling

Abstract Toll like receptors (TLRs) are a family of pattern recognition receptors that play a central role in pathogen recognition and shaping the innate immune response. While most of the studies of the role of TLRs have focused on mature immune cell populations, recent reports suggest that TLR signaling may regulate the immune response from the level of the hematopoietic stem cell (HSC). In this study, we sought to further elucidate the effects of systemic TLR ligand exposure on HSCs and determine the cell-intrinsic versus extrinsic effects of such exposure. We specifically focused on TLR2 signaling, as although TLR2 is expressed on HSCs, it’s role in their regulation is not clear. Furthermore, enhanced TLR2 signaling is associated with myelodysplastic syndrome (Wei et al, Leukemia 2013), suggesting that aberrant signaling through this receptor may have clinically significant effects on HSC function. To elucidate the role of TLR2 signaling in regulating HSCs, we used mice with genetic loss of TLR2, as well as a synthetic agonist of TLR2 (PAM3CSK4) to determine the effects of TLR2 signaling loss or gain, respectively, on HSC cycling, mobilization and function. While TLR2 expression is not required for normal HSC function, treatment of wild-type mice with PAM3CSK4 leads to expansion of HSCs in the bone marrow and spleen, increased HSC cycling, and loss of HSC function in competitive bone marrow transplantation experiments. As TLR2 is expressed on a variety of stromal and hematopoietic cell types, we used bone marrow chimeras (Tlr2-/- + Tlr2+/+ marrow transplanted into Tlr2+/+ recipients) to determine if the effects of PAM3CSK4 treatment are cell intrinsic or extrinsic. The data suggests that HSC cycling and expansion in the marrow and spleen upon PAM3CSK4 treatment are extrinsic (occurring in both transplanted HSC populations), and are associated with increased serum levels of G-CSF. Indeed, inhibition of G-CSF using either a neutralizing antibody or mice lacking the G-CSF receptor (Csf3r-/-) leads to even further enhanced HSC bone marrow expansion upon G-CSF treatment but significantly reduced numbers of spleen HSCs compared to similarly treated wild-type mice. This suggests mobilization in response to TLR2 signaling is an indirect, G-CSF-mediated process. Ongoing studies are aimed at determining the contribution of G-CSF to the PAM3CSK4- induced loss of HSC function, and determining the source (stromal vs hematopoietic) of G-CSF production upon PAM3CSK4 exposure. Collectively, this data suggest that TLR2 signaling affects HSCs in a largely extrinsic fashion, with G-CSF playing a major role in regulating the effects of TLR2 ligand exposure on HSCs. Disclosures No relevant conflicts of interest to declare.

The Concentration of CD44 Is Increased in Hematopoietic Stem Cell Grafts of Patients With Acute Myeloid Leukemia, Plasma Cell Myeloma, and Non-Hodgkin Lymphoma

2010 ◽  
Vol 134 (7) ◽  
pp. 1033-1038
Author(s):  
Daniela S. Krause ◽  
Thomas R. Spitzer ◽  
Christopher P. Stowell
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Clinical Outcome ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Hematologic Malignancies ◽  
Plasma Cell Myeloma ◽  
Malignant Cells ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Context.—In autologous hematopoietic stem cell transplantation (autoHSCT), malignant cells remaining in the graft may reengraft leading to relapse of the original disease. CD44 is known to play a role in the engraftment of leukemia-initiating cells and is shed from the surface of malignant cells. Soluble CD44 is a cleaved fragment, which is found in the serum of patients with metastasized epithelial and hematologic malignancies and in some other cancers, and has been demonstrated to be correlated with clinical outcome. Objectives.—To investigate (1) a possible correlation between the concentration of CD44 in an autoHSCT graft and the type of hematologic malignancy and (2) a possible correlation between the concentration of CD44 in the autoHSCT graft with clinical outcome after autoHSCT. Design.—We measured CD44 in 157 hematopoietic stem cell grafts from patients with hematologic malignancies and from 43 healthy donors by enzyme-linked immunosorbent assay. Results.—Levels of CD44 were almost 2-fold higher in the patients' grafts. Highest levels were found in the grafts of patients with acute myeloid leukemia, diffuse large B-cell lymphoma, and plasma cell myeloma, congruent with known CD44 expression levels in these malignancies. The survival advantage among patients with CD44 levels less than 22 000 ng/mL was highly statistically significant. Conclusion.—These results show that CD44 levels in an autoHSCT graft may be linked to clinical outcome after autoHSCT.

scholarly journals Magnesium levels and outcome after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia

2020 ◽  
Author(s):  
Linus Angenendt ◽  
Isabel Hilgefort ◽  
Jan-Henrik Mikesch ◽  
Bernhard Schlüter ◽  
Wolfgang E. Berdel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Epstein Barr Virus Infection ◽  
Hematopoietic Stem ◽  
Acute Myeloid

AbstractLow intake of magnesium has been associated with the occurrence of lymphomas and decreased magnesium levels suppress the cytotoxic function of T cells and natural killer cells in patients with “X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia” (XMEN) syndrome. These cell types are also important mediators of immune-mediated effects after allogeneic hematopoietic stem cell transplantation. Here, we show that high posttransplant magnesium levels independently associate with a lower incidence of relapse, a higher risk of acute graft-versus-host disease, and a higher non-relapse mortality in 368 patients with acute myeloid leukemia from our center. Magnesium serum levels might impact on donor-cell-mediated immune responses in acute myeloid leukemia.

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