scholarly journals The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence

Leukemia ◽  
2009 ◽  
Vol 23 (5) ◽  
pp. 892-899 ◽  
Author(s):  
I Bruns ◽  
A Czibere ◽  
J C Fischer ◽  
F Roels ◽  
R-P Cadeddu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Hematopoietic Stem Cell ◽  
Chronic Phase ◽  
Transcriptional Profile ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Critical Role Of Casein Kinase (Ck)1α Heterozygote Gene Inactivation In The Clonal Advantage Of Hematopoietic Stem Cells In Del(5q) MDS

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 98-98
Author(s):  
Rebekka K. Schneider ◽  
Dirk Heckl ◽  
Marcus Järås ◽  
Lisa Chu ◽  
McConkey Marie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor Cells ◽  
Stem And Progenitor Cells ◽  
A Cell

Abstract Casein kinase 1α (Ck1α) is a serine/threonine kinase located in the common deleted region (5q32) in del(5q) myelodysplastic syndrome (MDS). Ck1α is a regulator of the canonical WNT signaling pathway and may play a role in the clonal advantage of del(5q) cells. In addition, we identified CK1α as a therapeutic target in myeloid malignancies in an in vivo RNA interference screen, and haploinsufficiency for CK1α could further sensitize del(5q) cells to CK1α inhibition. To explore the biology and therapeutic potential of CK1α in MDS, we generated a conditional Ck1α knockout mouse model. Conditional homozygous inactivation of Ck1α resulted in bone marrow failure, ablation of hematopoietic stem and progenitor cells, a severe anemia and rapid lethality within 7-12 days, confirming that Ck1α is essential for hematopoietic stem and progenitor cell survival. In contrast, mice with haploinsufficiency of Ck1α developed a hypercellular bone marrow, as is typical in MDS, a significantly elevated white blood cell count (p=0.002) and normal hemoglobin levels. The hematopoietic stem cells (LSK, LT-HSC, ST-HSC) as well as progenitor cells (LK, pre-GMP, GMP, pre-CFU-e, CFU-e, pre-megakaryocytes-erythrocytes) were not affected by Ck1α haploinsufficiency 14 days after induction. Only the megakaryocytic progenitor cells (p=0.04) were significantly reduced. This finding was in line with severe dysplasia and hypolobulated micromegakaryocytes observed in the bone marrow, another typical histomorphological feature of del(5q) MDS. In long-term experiments up to 8 months, the survival of mice with Ck1α haploinsufficiency was not impaired, although we observed an exhaustion of the stem cell pool with significant reduction of ST-HSC (p<0.001), LT-HSC (p=0.003), and MPP (p=0.007). We were able to demonstrate that this significant reduction is a cell-extrinsic effect. In transplantation and HSC repopulation assays, an intact HSC function and even a significant expansion of hematopoietic stem cells and progenitor cells with Ck1α haploinsufficiency was confirmed in comparison to MxCre controls (LSK p=0.019; LK p=0.035; CMP p=0.036; GMP p=0.027; MEP p=0.005), suggesting a repopulation advantage of HSC with Ck1α haploinsufficiency. In contrast, Ck1α homozygous deletion leads to a cell-autonomous, p53-mediated HSC failure in transplantation assays. To dissect the mechanism of hematopoietic stem cell expansion in Ck1α haploinsufficiency on the one hand and the hematopoietic stem cell ablation after Ck1α ablation on the other hand, we analyzed regulatory mechanisms including proliferation and apoptosis in LK cells (myeloid progenitor cells) and LSK cells (enriched for hematopoietic stem cells). Ablation of Ck1α led to a significant increase (p=0.001) in the number of LSK and LK in the S/M/G2 phase, accompanied by a significant reduction in the G0/G1 fraction, suggesting their exit from quiescence. Ck1α haploinsufficiency led to a significant increase in the fraction of cycling cells in myeloid progenitor cells (LK, p=0.052), the quiescent hematopoietic stem cells were not significantly affected. In Western Blots of ckit+ hematopoietic stem and progenitor cells, a significant increase of intracellular ß-catenin levels was detected in both Ck1α haploinsufficient and even stronger in Ck1α ablated cells, accompanied by an exit from stem cell quiescence shown by loss of p21-mediated growth arrest and up-regulation of phosphorylated retinoblastoma protein indicating cell cycle progression from G0 to G1 in comparison to the MxCre+ control cells. Ck1α ablation led to p53-mediated apoptosis in stem and progenitor cells (Annexin V/7-AAD). In Ck1α haploinsufficient cells, apoptosis was not significantly induced in neither LK cells or in LSK cells although p53 induction was observed in the bone marrow. Taken together, our results indicate that Ck1α is essential for hematopoietic stem and progenitor cell survival, but that Ck1α haploinsufficiency does not decrease, and may increase, hematopoietic stem cell function. This finding highlights the potential of preferential elimination of the del(5q) hematopoietic stem cells through Ck1α inhibtion and thus provides a potential therapeutic window. Consistent with this hypothesis, targeting the haploinsufficient kinase activity in vitro with the Ck1α small molecule inhibitor D4476, selectively targets CK1α haploinsufficient cells relative to wild-type cells. Disclosures: Järås: Cantargia: Equity Ownership.

scholarly journals Lmo2Induces Hematopoietic Stem Cell-Like Features in T-Cell Progenitor Cells Prior to Leukemia

Stem Cells ◽  
2013 ◽  
Vol 31 (5) ◽  
pp. 882-894 ◽  
Author(s):  
Susan M. Cleveland ◽  
Stephen Smith ◽  
Rati Tripathi ◽  
Elizabeth M. Mathias ◽  
Charnise Goodings ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Progenitor Cells ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem

Abstract 20010: Diet-induced Obesity Stimulates Inflammatory Monopoiesis From Hematopoietic Stem Progenitor Cells Through Activating Histone Methylation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Milie Fang ◽  
Rita Mirza ◽  
Timothy J Koh ◽  
Norifumi Urao
Keyword(s):  
Progenitor Cells ◽  
Fold Increase ◽  
Control Mechanisms ◽  
Hematopoietic Stem ◽  
Fluorescent Intensity ◽  
Inflammatory Monocytes ◽  
Diet Induced Obesity ◽  
Histone 3 ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Obesity-induced monopoiesis has been implicated in the development of obesity-related complications. Monopoiesis is largely dependent on hematopoietic stem progenitor cells (HSPCs) in the bone marrow (BM). However, little is known about hematopoietic control mechanisms in diet-induced obesity. In a mouse model of diet-induced obesity (DIO), we found leukocytosis (9.465 ± 0.7350 K/ul versus 7.277 ± 0.3450 K/ul in healthy controls, n=7 each? , p=0.023) and increased inflammatory Ly6Chi monocytes in circulation (377.2 ± 40.94/ul vs. 224.8 ± 39.18/ul in lean control; n=7; p=0.023), associated with increased myeloid progenitor cells (60% increase in granulocyte-monocyte progenitor cells, n=4) in the BM. By flow cytometry based profiling, we found that active marks for transcription, histone 3 lysine 4 trimethylation (H3K4me3), are upregulated (1.82-fold increase in mean fluorescent intensity (MFI) vs. lean mice, n=5, p<0.05) in Ly6Chi inflammatory monocytes in DIO mice, along with increased inflammatory gene expression in response to TLR (toll-like receptor) 4 stimulation. In the BM, HSPCs but not myeloid progenitor cells have enriched H3K4me3 in DIO mice (2.84-fold in MFI in cKit+Sca1+Lin- cells, n=5, p<0.05). This activated mark in HSPCs is associated with increased monopoiesis from HSPCs (1.55-fold increase in output CD11b+Ly6Chi monocytes from cultured HSPCs, n=3-5, p<0.01) in response to TLR2 and TLR4 stimulations. Of note, HSPCs produce inflammatory cytokines to promote differentiation into inflammatory monocytes. Moreover, HIF-1a, a potential upstream of H3K4me3, is upregulated (2.29-fold in MFI, n=5, p<0.05) in HSPCs in DIO mice. These results suggest that obesity increases HIF-1a-mediated H3K4me3 enrichment in HSPCs, which in turn contributes to inflammatory cytokine expression and to increased inflammatory monopoiesis. Thus, epigenetic marks in HSPCs could be a target for obesity-related complications.

The histone lysine acetyltransferase HBO1 (KAT7) regulates hematopoietic stem cell quiescence and self-renewal

Blood ◽  
2021 ◽  
Author(s):  
Yuqing Yang ◽  
Andrew J Kueh ◽  
Zoe Grant ◽  
Waruni Abeysekera ◽  
Alexandra L Garnham ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Hematopoietic Stem Cell ◽  
Cell Function ◽  
Bone Marrow Cells ◽  
High Rate ◽  
Embryonic Patterning ◽  
Self Renewal ◽  
Hematopoietic Stem

The histone acetyltransferase HBO1 (MYST2, KAT7) is indispensable for postgastrulation development, histone H3 lysine 14 acetylation (H3K14Ac) and the expression of embryonic patterning genes. In this study, we report the role of HBO1 in regulating hematopoietic stem cell function in adult hematopoiesis. We used two complementary cre-recombinase transgenes to conditionally delete Hbo1 (Mx1-Cre and Rosa26-CreERT2). Hbo1 null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow two to six weeks after Hbo1 deletion. Hbo1 deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Hbo1 deletion caused a rapid loss of hematopoietic progenitors (HPCs). The numbers of lineage-restricted progenitors for the erythroid, myeloid, B-and T-cell lineages were reduced. Loss of HBO1 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, genes important for HSC functions were downregulated in HSC-enriched cell populations after Hbo1 deletion, including genes essential for HSC quiescence and self-renewal, such as Mpl, Tek(Tie-2), Gfi1b, Egr1, Tal1(Scl), Gata2, Erg, Pbx1, Meis1 and Hox9, as well as genes important for multipotent progenitor cells and lineage-specific progenitor cells, such as Gata1. HBO1 was required for H3K14Ac through the genome and particularly at gene loci required for HSC quiescence and self-renewal. Our data indicate that HBO1 promotes the expression of a transcription factor network essential for HSC maintenance and self-renewal in adult hematopoiesis.

scholarly journals Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2229-2236 ◽  
Author(s):  
MJ Robertson ◽  
RJ Soiffer ◽  
AS Freedman ◽  
SL Rabinowe ◽  
KC Anderson ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Red Blood Cell Transfusion ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Acute Myeloid

Abstract The CD33 antigen, identified by murine monoclonal antibody anti-MY9, is expressed by clonogenic leukemic cells from almost all patients with acute myeloid leukemia; it is also expressed by normal myeloid progenitor cells. Twelve consecutive patients with de novo acute myeloid leukemia received myeloablative therapy followed by infusion of autologous marrow previously treated in vitro with anti-MY9 and complement. Anti-MY9 and complement treatment eliminated virtually all committed myeloid progenitors (colony-forming unit granulocyte- macrophage) from the autografts. Nevertheless, in the absence of early relapse of leukemia, all patients showed durable trilineage engraftment. The median interval post bone marrow transplantation (BMT) required to achieve an absolute neutrophil count greater than 500/microL was 43 days (range, 16 to 75), to achieve a platelet count greater than 20,000/microL without transfusion was 92 days (range, 35 to 679), and to achieve red blood cell transfusion independence was 105 days (range, 37 to 670). At the time of BM harvest, 10 patients were in second remission, one patient was in first remission, and one patient was in third remission. Eight patients relapsed 3 to 18 months after BMT. Four patients transplanted in second remission remain disease-free 34+, 37+, 52+, and 57+ months after BMT. There was no treatment-related mortality. Early engraftment was significantly delayed in patients receiving CD33-purged autografts compared with concurrently treated patients receiving CD9/CD10-purged autografts for acute lymphoblastic leukemia or patients receiving CD6-purged allografts from HLA- compatible sibling donors. In contrast, both groups of autograft patients required a significantly longer time to achieve neutrophil counts greater than 500/microL and greater than 1,000/microL than did patients receiving normal allogeneic marrow. CD33(+)-committed myeloid progenitor cells thus appear to play an important role in the early phase of hematopoietic reconstitution after BMT. However, our results also show that human marrow depleted of CD33+ cells can sustain durable engraftment after myeloablative therapy, and provide further evidence that the CD33 antigen is absent from the human pluripotent hematopoietic stem cell.

The GEF Lsc Regulates Hematopoietic Stem Cell Motility, Mobilization and Recruitment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1346-1346
Author(s):  
Isabelle Petit ◽  
Prashant Kaul ◽  
Daniel J. Lerner ◽  
Shahin Rafii
Keyword(s):  
Stem Cell ◽  
Cell Migration ◽  
Tumor Growth ◽  
Cell Motility ◽  
Progenitor Cells ◽  
Hematopoietic Stem Cell ◽  
Tumor Angiogenesis ◽  
Progenitor Cell ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Abstract Lsc is a Rho GTPase guanine nucleotide exchange factor (RhoGEF) that physically and functionally links G-protein coupled receptors (GPCR) to the monomeric GTPase RhoA in mature hematopoietic and other cells. Lsc−/− (LscKO) mice have a peripheral leukocytosis, abnormal neutrophil and B cell motility, and immune response deficiencies. Although Lsc is required for neutrophil homeostasis, its role in hematopoietic stem and progenitor cells is unknown. In this study, we have used LscKO mice to determine if Lsc is required for normal stem cell motility and mobilization. Initially, we used immunofluorescence labeling to demonstrate that hematopoietic stem and progenitor cells express Lsc. This suggested that Lsc may be required for normal hematopoietic stem and progenitor cell migration. Stromal-cell derived factor-1 (SDF-1) is a potent chemokine for hematopoietic stem cells and activates the CXCR4 GPCR. It has been reported that Lsc is not required for SDF-1-stimulated migration of mature murine T and B cells. However, using a bare-filter transwell assay, we found that while LscKO Sca-1+ cells and Sca-1+Lin- cells have normal spontaneous migration, they have significantly increased SDF-1-stimulated migration compared to their wild-type (WT) counterparts, 1.4 and 2.3 fold, respectively. We then demonstrated that adhesion of LscKO Sca-1+ cells to bone marrow (BM) stromal MS-5 cells was normal, indicating that impaired adhesion was not responsible for the abnormal SDF-1-stimulated migration. Using colony assay, we demonstrated that LscKO mice have a normal number of circulating peripheral stem and progenitor cells. Strikingly, after 5 days of G-CSF administration, LscKO mice have 1.6 fold and 2.3 fold the number of peripheral mature WBC and stem and progenitor cells (colony forming units), respectively, compared to WT mice. Recruitment of BM CXCR4+ pro-angiogenic stem and progenitor cells has been linked to enhanced tumor angiogenesis. Because LscKO BM cells had abnormal SDF-1-stimulated migration and mobilization, we hypothesized that Lsc might regulate tumor angiogenesis as well. To this end, we assessed tumor growth in LscKO mice by injecting congenic Lewis lung carcinoma cells subcutaneously into LscKO mice and WT controls. Preliminary experiments revealed that tumors were 3.3 times larger in the LscKO mice as compared to WT mice. Quantification of the tumor vessels with anti-CD31 staining demonstrated that the tumors in LscKO mice were 1.4 fold more vascularized than controls. In summary, our results demonstrate that the Rho GEF Lsc is essential for normal hematopoietic stem cell migration and mobilization. In addition, we propose that absence of Lsc facilitates tumor growth by promoting BM stem and progenitor cell recruitment to the neo-angiogenic vessels, possibly augmenting tumor vascularization.

HoxA10 Regulates Myeloid Progenitor Proliferation by Activating Transcription of the Gene Encoding Transforming Growth Factor Beta 2.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1572-1572
Author(s):  
Chirag Shah ◽  
Hao Wang ◽  
Elizabeth A. Eklund
Keyword(s):  
Progenitor Cells ◽  
Transforming Growth Factor Beta ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Growth Factor Beta ◽  
Differentiation Block

Abstract Abstract 1572 HoxA10 is a homeodomain transcription factor which functions as a myeloid leukemia promoter. Correlative clinical studies found that increased expression of a group of HoxA proteins, including HoxA10, in acute myeloid leukemia (AML) was associated with poor prognosis. In murine models, overexpression of HoxA10 in the bone marrow was associated with development of a myeloproliferative disease which progressed to AML with time. These results suggested that HoxA10-overexpression dysregulated cell proliferation and/or survival, and predisposed to acquisition of additional mutations which led to differentiation block and AML. Additional investigations, we and others demonstrated that HoxA10 overexpression in murine hematopoietic stem cells (HSC) expanded the granulocyte/monocyte progenitor (GMP) population in vitro and in vivo. Despite this information about the impact of HoxA10 overexpression on myeloid leukemogenesis, the mechanisms by which HoxA10 exerts this effect are largely unknown. To investigate such mechanisms, we have been identifying HoxA10 target genes. In previous studies, we identified a number of HoxA10 target genes that encode phagocyte effector proteins. HoxA10 represses transcription of these gene in myeloid progenitors, and decreased HoxA10 repression activity contributes to phenotypic differentiation as myelopoiesis proceeds. This provided a potential mechanism for HoxA10 involvement in differentiation block, but not progenitor survival or expansion. We used a chromatin immuno-precipitation based approach to identify additional HoxA10 target genes involved in these activities. Previously, we reported that HoxA10 activated the DUSP4 gene in myeloid progenitor cells. This gene encodes Mitogen Activated Protein Kinase Phosphatase 2 (Mkp2) which inhibits Jnk-induced apoptosis in myeloid progenitor cells. This provided a mechanism for increased cell survival in HoxA10-overexpressing cells. In the current studies, we identified TGFB2 as a HoxA10 target gene. This gene encodes Transforming Growth Factor Beta 2 (TgfB2) a member of the TgfB super family of cytokines. Similar to TgfB1 and 3, TgfB2 interacts with TgfB-receptors I and II. However, unlike these more classical family members, TgfB2 induces proliferation of hematopoietic stem and progenitor cells. We found that HoxA10 activated the TGFB2 promoter via tandem cis elements in the proximal promoter. This resulted in autocrine stimulation of proliferation in HoxA10-overexpressing GMP and leukemia cells in vitro. Increased proliferation in HoxA10-overexpressing cells involved activation of the MAP kinase pathway in a TgfB2 dependent manner. These studies identify autocrine production of pro-proliferative cytokines as a novel mechanism for the function of Hox proteins. These findings have implications for ex vivo expansion of HSC and myeloid progenitors for tissue engineering. These result also have implications for therapeutic approaches to poor prognosis AML characterized by increased Hox expression. Disclosures: No relevant conflicts of interest to declare.

Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation For Patients With Chronic Myeloid Leukemia In Chronic Phase

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5518-5518
Author(s):  
Liu Xiaoli ◽  
Guanlun Gao ◽  
Xuan Zhou ◽  
Na Xu ◽  
Yajuan Xiao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Hematopoietic Stem ◽  
Risk Patients

Abstract Background and Objective Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib in treatment of chronic myeloid leukemia (CML) patients, the allogeneic hematopoietic stem cell transplantation (allo-HSCT) scene in CML has changed dramatically. This retrospective cohort study was designed to compare medical outcomes of Imatinib mesylate and allo-HSCT for patients with CML in chronic phase. Patients and Methods From February 2002 to February 2012, 198 patients treated consecutively at the Nanfang Hospital,Southern Medical University were assigned to two groups according to treatment with imatinib or allo-HSCT. One hundred fifteen cases of imatinib group were given imatinib at an initial dose of 400mg daily and the dose was then adjusted according to the patient´s blood and therapy response. All the patients were evaluated for hematologic, cytogenetic and molecular response every 1-3months. Eighty-three cases of allo-HSCT group received myeloablative preconditioning regimen, and methotrexate (MTX) and cyclosporine A (CsA) were used for graft-versus-host disease(GVHD), parts combined with mycophenolate mofetil (MMF) and antihuman thymocyte globulin(ATG). The primary end points of the study were complete cytogenetic response (CCyR), relapse rate, overall survival (OS) and progression-free survival (PFS) after therapy. Results In total, 59 (68.9%) patients treated over 12 months achieved a CCyR after 12 months in imatinib group, while 67 (95.7%) patients in allo-HSCT group. The relapse rates were 14.8% (n=17) in imatinib group and 10.8% (n=9) in allo-HSCT group (P=0.456). Ten-year cumulative OS rates were 93.9% in imatinib group and 77.1% in allo-HSCT group(P=0.015) and ten- year cumulative PFS rates of two groups were 86.1% vs.88.0%(P=0.508). For Sokal rating stratified analysis, the ten-year OS rates of two groups were 96.4% vs.68.0% (P = 0.049) for high-risk patients,92.6% vs. 57.1% (P = 0.019) for intermediate-risk patients , while the ten-year PFS rates of two groups were 89.3% vs. 88.0% for high-risk patients (P = 0.942), 70.4% vs. 85.7% for intermediate-risk patients (P = 0.405).The ten-year OS rates and PFS rates were not significant difference for low-risk patients. The cumulative OS rates of two groups were 94.7% vs. 73.5%(P=0.019)for the patients who were not less than 30 years old,and the cumulative PFS rates of two groups were 84.2% vs. 94.1% respectively (P=0.147). Conclusion Imatinib mesylate treatment is superior to allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in chronic phase. Disclosures: No relevant conflicts of interest to declare.

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