Modeling large fluctuations of thousands of clones during hematopoiesis: the role of stem cell self-renewal and bursty progenitor dynamics in rhesus macaque

AbstractIn a recent clone-tracking experiment, millions of uniquely tagged hematopoietic stem cells (HSCs) were autologously transplanted into rhesus macaques and peripheral blood containing thousands of tags were sampled and sequenced over 14 years to quantify the abundance of hundreds to thousands of tags or “clones.” Two major puzzles of the data have been observed: consistent differences and massive temporal fluctuations of clone populations. The large sample-to-sample variability can lead clones to occasionally go “extinct” but “resurrect” themselves in subsequent samples. Although heterogeneity in HSC differentiation rates, potentially due to tagging, and random sampling of the animals’ blood and cellular demographic stochasticity might be invoked to explain these features, we show that random sampling cannot explain the magnitude of the temporal fluctuations. Moreover, we show through simplerneutralmechanistic and statistical models of hematopoiesis of tagged cells that a broad distribution in clone sizes can arise from stochastic HSC self-renewal instead of tag-induced heterogeneity. The very large clone population fluctuations that often lead to extinctions and resurrections can be naturally explained by a generation-limited proliferation constraint on the progenitor cells. This constraint leads to bursty cell population dynamics underlying the large temporal fluctuations. We analyzed experimental clone abundance data using a new statistic that counts clonal disappearances and provide least-squares estimates of two key model parameters in our model, the total HSC differentiation rate and the maximum number of progenitor-cell divisions.Author summaryHematopoiesis of virally tagged cells in rhesus macaques is analyzed in the context of a mechanistic and statistical model. We find that the clone size distribution and the temporal variability in the abundance of each clone (viral tag) in peripheral blood are consistent with (i) stochastic HSC self-renewal during bone marrow repair, (ii) clonal aging that restricts the number of generations of progenitor cells, and (iii) infrequent and small-size samples. By fitting data, we infer two key parameters that control the level of fluctuations of clone sizes in our model: the total HSC differentiation rate and the maximum proliferation capacity of progenitor cells. Our analysis provides insight into the mechanisms of hematopoiesis and a framework to guide future multiclone barcoding/lineage tracking measurements.

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Disruption of the Normal Hematopoietic Hierarchy Leading to Stem Cell Exhaustion in an Animal Model of Myelodysplastic Syndrome

Blood ◽

10.1182/blood-2019-128707 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1698-1698

Author(s):

Yang Jo Chung ◽

Peter D. Aplan

Keyword(s):

Stem Cell ◽

Myelodysplastic Syndrome ◽

Progenitor Cells ◽

Peripheral Blood ◽

Fold Increase ◽

Brdu Incorporation ◽

Compensatory Mechanism ◽

Self Renewal ◽

Hematopoietic Stem

The ineffective hematopoiesis that is characteristic of myelodysplastic syndrome (MDS) suggests functional defects of hematopoietic stem and progenitor cells (HSPC). NUP98-HOXD13 (NHD13) transgenic mice recapitulate many features of human MDS such as ineffective hematopoiesis, peripheral blood cytopenias, dysplasia, and transformation to acute myeloid leukemia (AML), and have been used as a pre-clinical model for human MDS. NHD13 mice universally develop signs of MDS (e.g., peripheral blood cytopenia, macrocytosis, dysplasia) at approximately 5 months of age, with median survival of 10 months. Two month old NHD13 mice do not show clear evidence of MDS such as peripheral blood cytopenia, dysplasia, or transformation to AML. Bone marrow nucleated cells (BMNC) from two month old NHD13 mice have a modest 1.3-fold increase of lineage negative (LN) BMNCs compared to age matched WT mice. The increased number of LN BMNCs appeared to be primarily due to a 3.4-fold increase of the LN Sca-1+cKit-(LS+Kˉ) cells, an early lymphoid-committed precursor. Lineage negative Sca-1+ c-Kit+ (LSK) cells, which include the most immature, undifferentiated cells, can be divided into five sub populations, based on expression of Flk2, CD150, and CD48. These populations have been designated Long-Term Hematopoietic Stem Cell (LT-HSC), Short-Term HSC, (ST-HSC), and Multi-Potent Progenitor 2, 3, and 4 (MPP2, MPP3, and MPP4) based on functional assays. Two-month old NHD13 mice had decreased MPP4 (5-fold), decreased LT-HSC (3.6-fold) and increased ST-HSC (2.3-fold) compared with the age matched WT mice. The expansion of ST-HSC two-month old NHD13 mice was associated with increased cell proliferation of ST- HSC, as assessed by bromo-deoxy-uridine (BRDU) incorporation. We next studied LSK subsets from NHD13 mice aged seven months, which coincided with peripheral blood findings consistent with MDS (e.g. anemia, thrombocytopenia, macrocytosis), BM from seven month old NHD13 mice showed significant reductions of all LSK population subsets. LT-HSCs show differential expression of the CD41 antigen, and CD41ˉ LT-HSCs are more quiescent than CD41+ LT-HSCs and are thought to reside at the apex of the hematopoietic differentiation hierarchy. Although there was no difference in the absolute number of quiescent CD41ˉ LT-HSC between two and six month old WT mice, six month old NHD13 mice show a marked decrease (4.2 fold) in CD41ˉ LT-HSCs, suggesting exhaustion of LT-HSC in NHD13 mice. Colony forming assays were used to assess function of the five LSK sub-populations in vitro. LT-HSC and ST- HSC from NHD13 BMNC did not produce any colonies in two independent experiments, whereas MPP2 and MPP3 from NHD13 BMNC produced a similar number and lineage distribution of colonies compared to WT BMNC. This result suggested that HSCs from NHD13 BMNC may be functionally impaired, and that NHD13 hematopoietic progenitor cells may instead be derived primarily from MPP2 and MPP3. To evaluate HSC self-renewal activity, the five LSK subsets from NHD13 BMNC were transplanted to lethally irradiated mice together with 5 x 105 WT BMNC competitor cells. None of the NHD13 LSK sub-populations showed evidence of engraftment. Since NHD13 LN BMNC have previously been shown to be more prone to apoptosis than their WT counterpart, it is possible that lack of engraftment of NHD13 LSK subsets was due to the ex vivo sorting procedure. However, we also considered the possibility that NHD13 lineage positive (LP) BMNC had acquired self-renewal potential, and were contributing to long term hematopoiesis in the NHD13 BM. Therefore, we transplanted LP and LN BMNC from NHD13 or WT mice into WT recipients, again with WT competitor BMNC. Almost half of the NHD13 LP recipients showed long-term (>26 weeks) myeloid engraftment, whereas none of the WT LP recipients showed long term myeloid engraftment. Taken together, these findings suggest that the primitive LT-HSC (LSK Flk2ˉ CD150+CD48ˉ CD41ˉ) from NHD13 BM become exhausted with age, corresponding to the presentation of findings consistent with MDS (peripheral blood cytopenia, macrocytosis). Furthermore, self-renewal activity of NHD13 LP BMNCs suggest the existence of a compensatory mechanism for the homeostasis of hematopoiesis in MDS. Disclosures Aplan: NIH: Patents & Royalties: royalties for the invention of NUP98-HOXD13.

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Dual Role Of MERIT40 In Hematopoietic Stem and Progenitor Cells

Blood ◽

10.1182/blood.v122.21.797.797 ◽

2013 ◽

Vol 122 (21) ◽

pp. 797-797

Author(s):

Krasimira Rozenova ◽

Jing Jiang ◽

Chao Wu ◽

Junmin Wu ◽

Bernadette Aressy ◽

...

Keyword(s):

Bone Marrow ◽

Dna Damage ◽

Stem Cell ◽

Progenitor Cells ◽

Peripheral Blood ◽

Bone Marrow Failure ◽

Adaptor Protein ◽

Self Renewal ◽

Hematopoietic Stem

Abstract The balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) is maintained by cell intrinsic and extrinsic mechanisms, including tight regulation of signaling pathways such as Tpo-Mpl and SCF-ckit. Posttranslational modifications, such as phosphorylation and ubiquitination, regulate these pathways. While the role of protein phosphorylation is well established, the importance of ubiquitination in HSC self-renewal has not been well addressed. It is known that of the seven different lysines on ubiquitin, Lys48 polyubiquitination is a marker for protein degradation, and Lys63 polyubiquitination is associated with regulation of kinase activity, protein trafficking, and localization. In this study, we provide evidence that the adaptor protein MERIT40 has multiple roles in hematopoietic stem/progenitor cells (HSPCs). MERIT40 is a scaffolding protein shared by two distinct complexes with Lys63 deubiquitinase (DUB) activities: the nuclear RAP80 complex with a known role in DNA damage repair in breast/ovarian cancer cells, whereas the functions of the cytoplasmic BRISC remains less characterized. MERIT40 is important for integrity of both complexes, and its deficiency leads to their destabilization and a >90% reduction in deubiquitinase activity. By using MERIT40 knockout (M40-/-) mice, we found that lack of MERIT40 leads to a two-fold increase in phenotypic and functional HSCs determined by FACS and limiting dilution bone marrow transplantation (BMT), respectively. More importantly, M40-/- HSCs have increased regenerative capability demonstrated by increased chimerism in the peripheral blood after BMT of purified HSCs. The higher self-renewal potential of these HSCs provides a survival advantage to M40-/- mice and HSCs after repetitive administration of the cytotoxic agent 5-flurouracil (5FU). MERIT40 deficiency also preserves HSC stemness in culture as judged by an increase in peripheral blood chimerism in recipient mice transplanted with M40-/- Lin-Sca1+Kit+ (LSK) cells cultured in cytokines for nine days compared to recipient mice receiving cultured wildtype (WT) LSK cells. In contrast to the increased HSC homeostasis and superior stem cell activity due to MERIT40 deficiency, M40-/- mice are hypersensitive to DNA damaging agents caused by inter-cross linking (ICL), such as Mitomycin C (MMC) and acetaldehydes that are generated as side products of intracellular metabolism. MMC injection caused increased mortality in M40-/- mice compared to WT controls attributable to DNA damage-induced bone marrow failure. MMC-treated M40-/- mice showed marked reduction in LSK progenitor numbers accompanied by increased DNA damage, in comparison to WT mice. Consistent with the in vivo studies, M40-/- progenitor cells are hypersensitive to MMC and acetaldehyde treatment in a cell-autonomous manner in colony forming assays. ICL repair is known to require Fanconi Anemia (FA) proteins, an ICL repair network of which mutations in at least 15 different genes in humans cause bone marrow failure and cancer predisposition. Thus, M40-/- mice represent a novel mouse model to study ICL repair in HSPCs with potential relevance to bone marrow failure syndromes. Taken together, our data establishes a complex role of MERIT40 in HSPCs, warranting future investigation to decipher functional events downstream of two distinct deubiquitinating complexes associated with MERIT40 that may regulate distinct aspects of HSPC function. Furthermore, our findings reveal novel regulatory pathways involving a previously unappreciated role of K63-DUB in stem cell biology, DNA repair regulation and possibly bone marrow failure. DUBs are specialized proteases and have emerged as potential “druggable” targets for a variety of diseases. Hence, our work may provide insights into novel therapies for the treatment of bone marrow failure and associated malignancies that occur in dysregulated HSCs. Disclosures: No relevant conflicts of interest to declare.

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Clonal Features of Hematopoietic Stem and Progenitor Cells in Aging

Blood ◽

10.1182/blood.v126.23.243.243 ◽

2015 ◽

Vol 126 (23) ◽

pp. 243-243

Author(s):

Jianlong Sun ◽

Fernando D. Camargo

Keyword(s):

Blood Cell ◽

Progenitor Cells ◽

Peripheral Blood ◽

Cell Populations ◽

Multilineage Differentiation ◽

Self Renewal ◽

Hematopoietic Stem ◽

Cell Production ◽

Stem And Progenitor Cells

Abstract It is traditionally thought that Hematopoietic Stem Cells (HSCs) maintain blood homeostasis through long-term self-renewal and multilineage differentiation. This concept, however, is challenged by two recent studies in which the fundamental features of unperturbed hematopoiesis are evaluated by different approaches of lineage tracing. Both the kinetic analysis of HSC output by the Rodewald group and our clonal analysis with transposon barcoding suggest a dominant role of non-transplantable short-term HSCs and progenitors, but not the long-term HSCs, in driving native blood cell production. In addition, our longitudinal analysis of peripheral blood demonstrates extensive clonal succession in granulocyte production. These findings collectively suggest a distinct mechanism of native hematopoiesis that differs significantly from what has been learned in transplantation experiments. At the same time, they bring to light new questions regarding the ultimate fate of the progenitor population and the exact contribution of HSCs under normal physiological conditions. To address these questions, we examined clonal features of HSCs and progenitors in aged mice. Our results show a progressive reduction in clonal complexity and a concurrent increase in clonal stability when blood granulocytes are analyzed up to a hundred ten weeks after transposon barcoding. As time elapses, clonal overlapping between granulocytes and B cells become much more extensive, suggesting an increased tendency toward multilineage differentiation during aging. Analysis of stem and progenitor cells in bone marrow of aged mice reveals prevalent lineage output by multipotent progenitors (MPPs), whereas a lower fraction of HSC clones are found to produce mature progeny. While this overall pattern of differentiation is reminiscent of what has been observed in young and middle-aged animals, a two-fold increase in HSC clonal output was observed in these old mice, indicating their increased contribution to blood cell production. A comparison of clonal compositions in blood and marrow cell populations demonstrates an MPP origin of stable peripheral blood clones, and a smaller fraction of these clones can even be traced back to HSCs. These observations hence suggest extensive self-renewal and asymmetric cell division of these two cell populations in aging. Taken together, our results indicate that the aged hematopoietic system is characterized by reduced clonal complexity, increased clonal persistence, and HSC activation. The higher propensity to self-renewal during aging may also explain the elevated risk of malignant transformation in the elderly population. Disclosures Camargo: Cell Signaling Technologies: Consultancy; Vital Therapies: Consultancy.

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Loss of Krüppel-Like Factor 4 (KLF4) Leads to Increased Self-Renewal Under Stress Conditions and Improved Survival of Hematopoietic Stem Cells

Blood ◽

10.1182/blood.v118.21.861.861 ◽

2011 ◽

Vol 118 (21) ◽

pp. 861-861 ◽

Cited By ~ 1

Author(s):

Chun Shik Park ◽

Takeshi Yamada ◽

Koramit Suppipat ◽

Maksim Mamonkin ◽

H. Daniel Lacorazza

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Knockout Mice ◽

Peripheral Blood ◽

Fold Increase ◽

Ki 67 ◽

Self Renewal ◽

Hematopoietic Stem

Abstract Abstract 861 Hematopoiesis is a highly regulated process in which a small number of hematopoietic stem cells (HSC) generate all mature blood cells. In order to preserve homeostasis of the hematopoietic system throughout lifetime, this pool of HSC must be maintained by the processes of self-renewal and survival. Self-renewal requires a coordination of survival signals and control of proliferation uncoupled from differentiation. Even though extrinsic signals from the microenvironment and cell-intrinsic regulators are required for self-renewal of HSCs, the intricate transcriptional machinery that selectively regulates HSC self-renewal and survival is still poorly understood. Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor that regulates proliferation, differentiation, apoptosis, and self-renewal. The role of KLF4 in reprogramming adult somatic cells into pluripotent stem cells along with OCT3/4, c-Myc and SOX2 suggests that KLF4 is required for preservation of an undifferentiated state. To investigate the function of KLF4 in HSC maintenance, we used conditional Klf4 knockout mice (Klf4fl/flVav-iCre+) to specifically delete KLF4 gene in hematopoietic cells. We first analyzed the frequency of HSC and progenitor cells in the bone marrow (BM) of Klf4fl/flVav-iCre– (control) and Klf4fl/flVav-iCre+ (knockout) by flow cytometry. We found that KLF4 deficiency leads to a 2.4-fold increase in the number of long-term HSC (Lin–Sca-1+c-Kit+ CD150+ CD48–) and a 2.2-fold increase in short-term HSC compartements (Lin–Sca-1+c-Kit+ CD150+ CD48+) whereas no significant changes were found in myeloid and lymphoid progenitor cells. Consistent with this phenotypic analysis, KLF4 expression in HSC is higher than hematopoietic progenitor cells and mature lineages (n=3; P<0.05). Even though ablation of Klf4 gene does not affect multi-lineage potential of HSC upon transplantation, its deletion leads to a reduction of monocytes and T cell expansion. To assess the effect of Klf4 ablation in self-renewal, we performed serial competitive repopulation assays using a 1:1 mixture of BM cells from control (Klf4fl/flVav-iCre–; CD45.2+) or knockout (Klf4fl/flVav-iCre+; CD45.2+) with B6.SJL (CD45.1+) mice. In primary transplants, the contribution of knockout BM cells in peripheral blood was similar to controls. Interestingly, loss of KLF4 led to enhanced contribution to peripheral blood in secondary transplants (4.5-fold; P<0.005) and tertiary transplants (2.6-fold; P<0.005). Consistent with this result, we found a significant increased number of colony forming units only in the third replating on methylcellulose (P<0.0005). To further characterize the role of KLF4 in HSC proliferation, we determined expression of Ki-67 and DNA content in nuclei of LSK CD150+ cells. The fraction of G0 cells defined as Ki-67– within 2n DNA in Klf4-knockout LSK CD150+ cells was similar to control (control 74.3 ± 0.7% vs 73.2 ± 2.3%). However, Annexin V staining revealed a 2.4-fold increased survival of LSK CD150+ cells in Klf4-knockout mice compared to control mice but not in myeloid progenitor cells (Lin–c-Kit+Sca-1–) suggesting that KLF4 selectively regulates the survival of HSC. These studies indicate that KLF4 controls steady state HSC survival and self-renewal under stress conditions. Disclosures: No relevant conflicts of interest to declare.

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Ex vivo expansion of human hematopoietic stem and progenitor cells

Blood ◽

10.1182/blood-2011-01-283606 ◽

2011 ◽

Vol 117 (23) ◽

pp. 6083-6090 ◽

Cited By ~ 187

Author(s):

Ann Dahlberg ◽

Colleen Delaney ◽

Irwin D. Bernstein

Keyword(s):

Stem Cell ◽

Growth Factors ◽

Notch Signaling ◽

Progenitor Cells ◽

Ex Vivo ◽

Ex Vivo Expansion ◽

Hematopoietic Growth Factors ◽

Self Renewal ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells

AbstractDespite progress in our understanding of the growth factors that support the progressive maturation of the various cell lineages of the hematopoietic system, less is known about factors that govern the self-renewal of hematopoietic stem and progenitor cells (HSPCs), and our ability to expand human HSPC numbers ex vivo remains limited. Interest in stem cell expansion has been heightened by the increasing importance of HSCs in the treatment of both malignant and nonmalignant diseases, as well as their use in gene therapy. To date, most attempts to ex vivo expand HSPCs have used hematopoietic growth factors but have not achieved clinically relevant effects. More recent approaches, including our studies in which activation of the Notch signaling pathway has enabled a clinically relevant ex vivo expansion of HSPCs, have led to renewed interest in this arena. Here we briefly review early attempts at ex vivo expansion by cytokine stimulation followed by an examination of our studies investigating the role of Notch signaling in HSPC self-renewal. We will also review other recently developed approaches for ex vivo expansion, primarily focused on the more extensively studied cord blood–derived stem cell. Finally, we discuss some of the challenges still facing this field.

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Circulating CD34+ hematopoietic stem/progenitor cells paralleled with level of viremia in patients chronically infected with hepatitis B virus

Regenerative Medicine Research ◽

10.1051/rmr/170005 ◽

2018 ◽

Vol 6 ◽

pp. 1 ◽

Cited By ~ 1

Author(s):

Hussein Abdellatif

Keyword(s):

Viral Load ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Progenitor Cells ◽

Peripheral Blood ◽

Healthy Controls ◽

Hematopoietic Stem ◽

Study Results ◽

Viremia Level ◽

B Virus

Introduction: Liver regeneration is a heterogeneous process involving proliferation of different cell types in response to injury. Bone marrow derived stem cells may be involved in this process, by making contribution to parenchymal restoration and cellular replacement. We aimed to investigate the correlation between level of circulating mobilized CD34+ hematopoietic stem progenitor cells (HSPCs) and viremia level in patients chronically infected with hepatitis B virus (HBV). Methods: Blood samples were prospectively collected for assessing percentage and absolute counts of circulating CD34+ HSPCs and viral load level using flow cytometry and RT-PCR respectively. Patients with chronic hepatitis B (CHB) (n = 30), Entecavir (ETV) treated subjects (n = 30) and 20 age and gender matched healthy controls were enrolled in this study. Results were expressed as mean ± SD. Results and discussion: A significant increase in circulating CD34+ HSPCs level was observed in CHB patients (5 ± 3.1, 324 ± 195 × 103/ml) as compared to ETV treated subjects (0.57 ± 0.27,1022 ± 325) and healthy controls (0.53 ± 0.37, 694 ± 254, P < 0.001) in regards to percentage and absolute counts respectively. Levels of CD34+ HSPCs strongly and positively correlated with HBV DNA viral load levels in CHB patients (r2 = 0.8417, 0.649, P < 0.001).Thus, in chronic liver disorders (CHB), when reduced regenerative capacity of hepatocytes is reached, BMSCs mobilization occurs and their level increases in peripheral blood. The level of circulating CD34+ cells in peripheral blood of CHB patients paralleled with the hepatitis B viral load.

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

Blood ◽

10.1182/blood.2021013954 ◽

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.

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Polyclonal Long-Term MFGS-gp91phox Marking in Rhesus Macaques after Nonmyeloablative Transplantation with Transduced Autologous Peripheral Blood Progenitor Cells

Molecular Therapy ◽

10.1016/j.ymthe.2006.01.015 ◽

2006 ◽

Vol 14 (2) ◽

pp. 202-211 ◽

Cited By ~ 9

Author(s):

Sebastian Brenner ◽

Martin F. Ryser ◽

Uimook Choi ◽

Narda Whiting-Theobald ◽

Eberhard Kuhlisch ◽

...

Keyword(s):

Progenitor Cells ◽

Peripheral Blood ◽

Rhesus Macaques ◽

Peripheral Blood Progenitor Cells

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Mouse acute leukemia develops independent of self-renewal and differentiation potentials in hematopoietic stem and progenitor cells

Blood Advances ◽

10.1182/bloodadvances.2018022400 ◽

2019 ◽

Vol 3 (3) ◽

pp. 419-431 ◽

Cited By ~ 7

Author(s):

Fang Dong ◽

Haitao Bai ◽

Xiaofang Wang ◽

Shanshan Zhang ◽

Zhao Wang ◽

...

Keyword(s):

Stem Cells ◽

Acute Leukemia ◽

Progenitor Cells ◽

Lymphoblastic Leukemia ◽

The Self ◽

Myelogenous Leukemia ◽

Mouse Bone Marrow ◽

Self Renewal ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells

Abstract The cell of origin, defined as the normal cell in which the transformation event first occurs, is poorly identified in leukemia, despite its importance in understanding of leukemogenesis and improving leukemia therapy. Although hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were used for leukemia models, whether their self-renewal and differentiation potentials influence the initiation and development of leukemia is largely unknown. In this study, the self-renewal and differentiation potentials in 2 distinct types of HSCs (HSC1 [CD150+CD41−CD34−Lineage−Sca-1+c-Kit+ cells] and HSC2 [CD150−CD41−CD34−Lineage−Sca-1+c-Kit+ cells]) and 3 distinct types of HPCs (HPC1 [CD150+CD41+CD34−Lineage−Sca-1+c-Kit+ cells], HPC2 [CD150+CD41+CD34+Lineage−Sca-1+c-Kit+ cells], and HPC3 [CD150−CD41−CD34+Lineage−Sca-1+c-Kit+ cells]) were isolated from adult mouse bone marrow, and examined by competitive repopulation assay. Then, cells from each population were retrovirally transduced to initiate MLL-AF9 acute myelogenous leukemia (AML) and the intracellular domain of NOTCH-1 T-cell acute lymphoblastic leukemia (T-ALL). AML and T-ALL similarly developed from all HSC and HPC populations, suggesting multiple cellular origins of leukemia. New leukemic stem cells (LSCs) were also identified in these AML and T-ALL models. Notably, switching between immunophenotypical immature and mature LSCs was observed, suggesting that heterogeneous LSCs play a role in the expansion and maintenance of leukemia. Based on this mouse model study, we propose that acute leukemia arises from multiple cells of origin independent of the self-renewal and differentiation potentials in hematopoietic stem and progenitor cells and is amplified by LSC switchover.

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