Differential regulation of myeloid leukemias by the bone marrow microenvironment
TL;DR: It is demonstrated that LSC niches in CML and AML are distinct and suggested that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML.
Abstract: Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSC) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM)1, and may be the cause of relapse following chemotherapy.2 Targeting the niche is a novel strategy to eliminate persistent and drug-resistant LSC. CD443,4 and IL-65 have been implicated previously in the LSC niche. Transforming growth factor (TGF)-β1 is released during bone remodeling6 and plays a role in maintenance of CML LSCs7, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor8,9 attenuates BCR-ABL1-induced CML-like myeloproliferative neoplasia (MPN)10 but enhances MLL-AF9-induced AML11 in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSC. PTH treatment caused a 15-fold decrease in LSCs in wildtype mice with CML-like MPN, and reduced engraftment of immune deficient mice with primary human CML cells. These results demonstrate that LSC niches in chronic and acute myeloid leukemias are distinct, and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSC, a prerequisite for the cure of CML.
Citations
More filters
TL;DR: Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK–STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche.
Abstract: The Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins, particularly STAT3, are among the most promising new targets for cancer therapy. In addition to interleukin-6 (IL-6) and its family members, multiple pathways, including G-protein-coupled receptors (GPCRs), Toll-like receptors (TLRs) and microRNAs were recently identified to regulate JAK-STAT signalling in cancer. Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK-STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche. In addition to its established role as a transcription factor in cancer, STAT3 regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms. Newly identified regulators and functions of JAK-STAT3 in tumours are important targets for potential therapeutic strategies in the treatment of cancer.
1,572 citations
TL;DR: Advances in understanding of HSC regulation by niches during homeostasis, ageing and cancer are reviewed and their implications for the development of therapies to rejuvenate aged HSCs or niches or to disrupt self-reinforcing malignant niches are discussed.
Abstract: The haematopoietic stem cell (HSC) microenvironment in the bone marrow, termed the niche, ensures haematopoietic homeostasis by controlling the proliferation, self-renewal, differentiation and migration of HSCs and progenitor cells at steady state and in response to emergencies and injury. Improved methods for HSC isolation, driven by advances in single-cell and molecular technologies, have led to a better understanding of their behaviour, heterogeneity and lineage fate and of the niche cells and signals that regulate their function. Niche regulatory signals can be in the form of cell-bound or secreted factors and other local physical cues. A combination of technological advances in bone marrow imaging and genetic manipulation of crucial regulatory factors has enabled the identification of several candidate cell types regulating the niche, including both non-haematopoietic (for example, perivascular mesenchymal stem and endothelial cells) and HSC-derived (for example, megakaryocytes, macrophages and regulatory T cells), with better topographical understanding of HSC localization in the bone marrow. Here, we review advances in our understanding of HSC regulation by niches during homeostasis, ageing and cancer, and we discuss their implications for the development of therapies to rejuvenate aged HSCs or niches or to disrupt self-reinforcing malignant niches. The haematopoietic stem cell (HSC) niche in the bone marrow ensures haematopoiesis by regulating the function of HSCs and progenitor cells. An improved understanding of this regulation in homeostasis, ageing and cancer should aid the development of therapies to rejuvenate aged HSCs or niches and treat malignancies.
529 citations
TL;DR: A dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress is reported, demonstrating that MKs serve as HSC-derived niche cells to dynamically regulate HSC function.
Abstract: Multiple bone marrow stromal cell types have been identified as hematopoietic stem cell (HSC)-regulating niche cells. However, whether HSC progeny can serve directly as HSC niche cells has not previously been shown. Here we report a dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress. We show that MKs are physically associated with HSCs in the bone marrow of mice and that MK ablation led to activation of quiescent HSCs and increased HSC proliferation. RNA sequencing (RNA-seq) analysis revealed that transforming growth factor β1 (encoded by Tgfb1) is expressed at higher levels in MKs as compared to other stromal niche cells. MK ablation led to reduced levels of biologically active TGF-β1 protein in the bone marrow and nuclear-localized phosphorylated SMAD2/3 (pSMAD2/3) in HSCs, suggesting that MKs maintain HSC quiescence through TGF-β-SMAD signaling. Indeed, TGF-β1 injection into mice in which MKs had been ablated restored HSC quiescence, and conditional deletion of Tgfb1 in MKs increased HSC activation and proliferation. These data demonstrate that TGF-β1 is a dominant signal emanating from MKs that maintains HSC quiescence. However, under conditions of chemotherapeutic challenge, MK ablation resulted in a severe defect in HSC expansion. In response to stress, fibroblast growth factor 1 (FGF1) signaling from MKs transiently dominates over TGF-β inhibitory signaling to stimulate HSC expansion. Overall, these observations demonstrate that MKs serve as HSC-derived niche cells to dynamically regulate HSC function.
468 citations
TL;DR: How genetic changes in stromal cells and leukemia-induced BM niche remodeling contribute to blood malignancies are described and how these findings can be applied to non-cell-autonomous therapies targeting the LSC niche are discussed.
348 citations
TL;DR: Recent data is reviewed on the cellular constituents and molecular mechanisms involved in the communication between HSCs and putative niches that regulate HSC quiescence and the supply of lineage-committed progenitors.
342 citations
Cites result from "Differential regulation of myeloid ..."
...Similar expansion of MSPCs has recently been reported for AML which destroys sympathetic nerves in bone marrow and spleen that are infiltrated with AML....
[...]
...Distinct signals in the microenvironment may also differentially alter malignant transformation, as suggested by the expression of a constitutively active PTH receptor in osteoblasts that inhibits chronic myelogenous leukemia (CML)-like myeloproliferation while enhancing MLL-AF9–driven AML.(108) MSPC differentiation toward the osteoblastic lineage in BCR-ABL CML results in increased mature osteoblast numbers(99) in contrast to BCR-ABL CML blast crisis....
[...]
References
More filters
TL;DR: Osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation.
Abstract: Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by gamma-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.
3,434 citations
"Differential regulation of myeloid ..." refers methods in this paper
...For the daily subcutaneous injections (intermittent dosing regimen), we administered human PTH (1-34) or saline at 80 μg per kg body weight per day....
[...]
...We also transduced WT BM with retrovirus expressing MLLMLLT3 (here referred to as MLL-AF9), the product of human t(9;11)+ AML, which induces aggressive AML in mice11....
[...]
...For the secondary transplantation in the BALB/c background (limiting dilution experiment), we treated primary WT BALB/c mice with saline and human PTH (1-34) by osmotic minipump for 4 weeks before transplantation with BCR-ABL1+ cells....
[...]
TL;DR: It is demonstrated that P210bcr/abl expression can induce chronic myelogenous leukemia and retrovirus-mediated expression of the protein provides a murine model system for further analysis of the disease.
Abstract: In tumor cells from virtually all patients with chronic myelogenous leukemia, the Philadelphia chromosome, a fusion of chromosomes 9 and 22, directs the synthesis of the P210bcr/abl protein. The protein-tyrosine kinase activity and hybrid structure of P210bcr/abl are similar to the oncogene product of the Abelson murine leukemia virus, P160gag/v-abl, which induces acute lymphomas. To determine whether P210bcr/abl can induce chronic myelogenous leukemia, murine bone marrow was infected with a retrovirus encoding P210bcr/abl and transplanted into irradiated syngeneic recipients. Transplant recipients developed several hematologic malignancies; prominent among them was a myeloproliferative syndrome closely resembling the chronic phase of human chronic myelogenous leukemia. Tumor tissue from diseased mice harbored the provirus encoding P210bcr/abl. These results demonstrate that P210bcr/abl expression can induce chronic myelogenous leukemia. Retrovirus-mediated expression of the protein provides a murine model system for further analysis of the disease.
2,199 citations
"Differential regulation of myeloid ..." refers methods in this paper
...For the daily subcutaneous injections (intermittent dosing regimen), we administered human PTH (1-34) or saline at 80 μg per kg body weight per day....
[...]
...For the secondary transplantation in the BALB/c background (limiting dilution experiment), we treated primary WT BALB/c mice with saline and human PTH (1-34) by osmotic minipump for 4 weeks before transplantation with BCR-ABL1+ cells....
[...]
TL;DR: It is shown that leukaemia stem cells (LSC) can maintain the global identity of the progenitor from which they arose while activating a limited stem-cell- or self-renewal-associated programme.
Abstract: Leukaemias and other cancers possess a rare population of cells capable of the limitless self-renewal necessary for cancer initiation and maintenance. Eradication of these cancer stem cells is probably a critical part of any successful anti-cancer therapy, and may explain why conventional cancer therapies are often effective in reducing tumour burden, but are only rarely curative. Given that both normal and cancer stem cells are capable of self-renewal, the extent to which cancer stem cells resemble normal tissue stem cells is a critical issue if targeted therapies are to be developed. However, it remains unclear whether cancer stem cells must be phenotypically similar to normal tissue stem cells or whether they can retain the identity of committed progenitors. Here we show that leukaemia stem cells (LSC) can maintain the global identity of the progenitor from which they arose while activating a limited stem-cell- or self-renewal-associated programme. We isolated LSC from leukaemias initiated in committed granulocyte macrophage progenitors through introduction of the MLL-AF9 fusion protein encoded by the t(9;11)(p22;q23). The LSC were capable of transferring leukaemia to secondary recipient mice when only four cells were transferred, and possessed an immunophenotype and global gene expression profile very similar to that of normal granulocyte macrophage progenitors. However, a subset of genes highly expressed in normal haematopoietic stem cells was re-activated in LSC. LSC can thus be generated from committed progenitors without widespread reprogramming of gene expression, and a leukaemia self-renewal-associated signature is activated in the process. Our findings define progression from normal progenitor to cancer stem cell, and suggest that targeting a self-renewal programme expressed in an abnormal context may be possible.
1,406 citations
"Differential regulation of myeloid ..." refers methods in this paper
...For the daily subcutaneous injections (intermittent dosing regimen), we administered human PTH (1-34) or saline at 80 μg per kg body weight per day....
[...]
...We also transduced WT BM with retrovirus expressing MLLMLLT3 (here referred to as MLL-AF9), the product of human t(9;11)+ AML, which induces aggressive AML in mice11....
[...]
...For the secondary transplantation in the BALB/c background (limiting dilution experiment), we treated primary WT BALB/c mice with saline and human PTH (1-34) by osmotic minipump for 4 weeks before transplantation with BCR-ABL1+ cells....
[...]
TL;DR: It is demonstrated that absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted, and mechanisms underlying this eradication included interference with transport to stem cell–supportive microenvironmental niches and alteration of AML-LSC fate.
Abstract: The long-term survival of patients with acute myeloid leukemia (AML) is dismally poor. A permanent cure of AML requires elimination of leukemic stem cells (LSCs), the only cell type capable of initiating and maintaining the leukemic clonal hierarchy. We report a therapeutic approach using an activating monoclonal antibody directed to the adhesion molecule CD44. In vivo administration of this antibody to nonobese diabetic-severe combined immune-deficient mice transplanted with human AML markedly reduced leukemic repopulation. Absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted. Mechanisms underlying this eradication included interference with transport to stem cell-supportive microenvironmental niches and alteration of AML-LSC fate, identifying CD44 as a key regulator of AML LSCs. The finding that AML LSCs require interaction with a niche to maintain their stem cell properties provides a therapeutic strategy to eliminate quiescent AML LSCs and may be applicable to other types of cancer stem cells.
1,164 citations
"Differential regulation of myeloid ..." refers methods in this paper
...For the daily subcutaneous injections (intermittent dosing regimen), we administered human PTH (1-34) or saline at 80 μg per kg body weight per day....
[...]
...For the secondary transplantation in the BALB/c background (limiting dilution experiment), we treated primary WT BALB/c mice with saline and human PTH (1-34) by osmotic minipump for 4 weeks before transplantation with BCR-ABL1+ cells....
[...]
TL;DR: Hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability, and BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemoJuvelin and blunted in Hfe2−/− hepatocytes.
Abstract: Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.
1,000 citations
"Differential regulation of myeloid ..." refers methods in this paper
...For the daily subcutaneous injections (intermittent dosing regimen), we administered human PTH (1-34) or saline at 80 μg per kg body weight per day....
[...]
...For the secondary transplantation in the BALB/c background (limiting dilution experiment), we treated primary WT BALB/c mice with saline and human PTH (1-34) by osmotic minipump for 4 weeks before transplantation with BCR-ABL1+ cells....
[...]