ABSTRACT
ABSTRACT: The spectrum of myeloid disorders ranges from aplastic bone marrow failure characterized by an empty bone marrow completely lacking in hematopoiesis to acute myeloid leukemia in which the marrow space is replaced by undifferentiated leukemic blasts. Recent advances in the capacity to sequence bulk tumor population as well as at a single-cell level has provided significant insight into the stepwise process of transformation to acute myeloid leukemia. Using models of progression in the context of germ line predisposition (trisomy 21, GATA2 deficiency, and SAMD9/9L syndrome), premalignant states (clonal hematopoiesis and clonal cytopenia of unknown significance), and myelodysplastic syndrome, we review the mechanisms of progression focusing on the hierarchy of clonal mutation and potential roles of transcription factor alterations, splicing factor mutations, and the bone marrow environment in progression to acute myeloid leukemia. Despite major advances in our understanding, preventing the progression of these disorders or treating them at the acute leukemia phase remains a major area of unmet medical need.
Subject(s)
Disease Progression , Humans , Preleukemia/pathology , Preleukemia/genetics , Myelodysplastic Syndromes/pathology , Myelodysplastic Syndromes/genetics , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/genetics , Animals , Precancerous Conditions/pathology , Precancerous Conditions/genetics , Mutation , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Cell Transformation, Neoplastic/metabolismABSTRACT
Acute myeloid leukemia (AML) arises from preleukemic conditions. We have investigated the pathogenesis of typical preleukemia, myeloproliferative neoplasms, and clonal hematopoiesis. Hematopoietic stem cells in both preleukemic conditions harbor recurrent driver mutations; additional mutation provokes further malignant transformation, leading to AML onset. Although genetic alterations are defined as the main cause of malignant transformation, non-genetic factors are also involved in disease progression. In this review, we focus on a non-histone chromatin protein, high mobility group AT-hook2 (HMGA2), and a physiological p53 inhibitor, murine double minute X (MDMX). HMGA2 is mainly overexpressed by dysregulation of microRNAs or mutations in polycomb components, and provokes expansion of preleukemic clones through stem cell signature disruption. MDMX is overexpressed by altered splicing balance in myeloid malignancies. MDMX induces leukemic transformation from preleukemia via suppression of p53 and p53-independent activation of WNT/ß-catenin signaling. We also discuss how these non-genetic factors can be targeted for leukemia prevention therapy.
Subject(s)
Leukemia, Myeloid, Acute , Preleukemia , Animals , Mice , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/pathology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Mutation , Preleukemia/genetics , Preleukemia/pathology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
Transcriptional variability facilitates stochastic cell diversification and can in turn underpin adaptation to stress or injury. We hypothesize that it may analogously facilitate progression of premalignancy to cancer. To investigate this, we initiated preleukemia in mouse cells with enhanced transcriptional variability due to conditional disruption of the histone lysine acetyltransferase gene Kat2a. By combining single-cell RNA sequencing of preleukemia with functional analysis of transformation, we show that Kat2a loss results in global variegation of cell identity and accumulation of preleukemic cells. Leukemia progression is subsequently facilitated by destabilization of ribosome biogenesis and protein synthesis, which confer a transient transformation advantage. The contribution of transcriptional variability to early cancer evolution reflects a generic role in promoting cell fate transitions, which, in the case of well-adapted malignancies, contrastingly differentiates and depletes cancer stem cells. That is, transcriptional variability confers forward momentum to cell fate systems, with differential multistage impact throughout cancer evolution.
Subject(s)
Leukemia , Preleukemia , Animals , Cell Differentiation , Leukemia/genetics , Mice , Preleukemia/genetics , Preleukemia/pathology , Protein BiosynthesisABSTRACT
Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a "multi-step" or "multi-hit" mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating events, such as chromosomal translocations, originate in utero, and studies so far suggest that these "first-hits" occur at a far higher frequency than the incidence of childhood leukemia itself. The reason why only a small percentage of the children born with such preleukemic "hits" will develop full-blown leukemia is still a mystery. In order to better understand childhood leukemia, mouse modeling is essential, but only if the multistage process of leukemia can be recapitulated in the model. Therefore, mouse models naturally reproducing the "multi-step" process of childhood B-ALL will be essential to identify environmental or other factors that are directly linked to increased risk of disease.
Subject(s)
Myelodysplastic Syndromes , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Preleukemia , Animals , Disease Models, Animal , Humans , Mice , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Preleukemia/genetics , Translocation, GeneticABSTRACT
Preleukemic has been used to describe children with a propensity to develop B cell acute lymphoblastic leukemia (B-ALL). However, leukemia-predisposing mutations can also be present in differentiated cells unable to transform. We postulate that preleukemia should only be used when such mutations arise in progenitors capable of evolving to B-ALL.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma , Preleukemia , Child , Humans , Preleukemia/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , MutationABSTRACT
Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.
Subject(s)
Cell Cycle Proteins/genetics , Down Syndrome/genetics , GATA1 Transcription Factor/genetics , Hematopoietic Stem Cells/physiology , Leukemia, Myeloid/genetics , Preleukemia/genetics , Animals , Antigens, CD34/analysis , Cell Cycle Proteins/metabolism , Cell Lineage , Cell Proliferation , Cell Transformation, Neoplastic , Chromosomal Proteins, Non-Histone/genetics , Chromosomes, Human, Pair 21/genetics , Chromosomes, Human, Pair 21/metabolism , Disease Models, Animal , Disease Progression , Down Syndrome/complications , Female , GATA1 Transcription Factor/metabolism , Hematopoiesis , Hematopoietic Stem Cell Transplantation , Heterografts , Humans , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/pathology , Liver/embryology , Male , Megakaryocytes/physiology , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Mutation , Preleukemia/metabolism , Preleukemia/pathology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Mas , Proto-Oncogene Proteins c-kit/analysis , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , CohesinsABSTRACT
t(4;11) MLL-AF4 acute leukemia is one of the most aggressive malignancies in the infant and pediatric population, yet we have little information on the molecular mechanisms responsible for disease progression. This impairs the development of therapeutic regimens that can address the aggressive phenotype and lineage plasticity of MLL-AF4-driven leukemogenesis. This study highlights novel mechanisms of disease development by focusing on 2 microRNAs (miRNAs) upregulated in leukemic blasts from primary patient samples: miR-130b and miR-128a. We show that miR-130b and miR-128a are downstream targets of MLL-AF4 and can individually drive the transition from a pre-leukemic stage to an acute leukemia in an entirely murine Mll-AF4 in vivo model. They are also required to maintain the disease phenotype. Interestingly, miR-130b overexpression led to a mixed/B-cell precursor (BCP)/myeloid leukemia, propagated by the lymphoid-primed multipotent progenitor (LMPP) population, whereas miR-128a overexpression resulted in a pro-B acute lymphoblastic leukemia (ALL), maintained by a highly expanded Il7r+c-Kit+ blast population. Molecular and phenotypic changes induced by these two miRNAs fully recapitulate the human disease, including central nervous system infiltration and activation of an MLL-AF4 expression signature. Furthermore, we identified 2 downstream targets of these miRNAs, NR2F6 and SGMS1, which in extensive validation studies are confirmed as novel tumor suppressors of MLL-AF4+ leukemia. Our integrative approach thus provides a platform for the identification of essential co-drivers of MLL-rearranged leukemias, in which the preleukemia to leukemia transition and lineage plasticity can be dissected and new therapeutic approaches can be tested.
Subject(s)
Leukemia, Myeloid, Acute/genetics , MicroRNAs/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Animals , Cell Line, Tumor , DNA-Binding Proteins/genetics , Female , Gene Expression Regulation, Leukemic , Humans , Male , Mice , Preleukemia/genetics , Transcriptional Elongation Factors/genetics , Translocation, GeneticABSTRACT
B cell acute lymphoblastic leukaemia (B-ALL) is the most common form of childhood cancer. Although treatment has advanced remarkably in the past 50 years, it still fails in ~20% of patients. Recent studies revealed that more than 5% of healthy newborns carry preleukaemic clones that originate in utero, but only a small percentage of these carriers will progress to overt B-ALL. The drivers of progression are unclear, but B-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. Emerging evidence shows that a major driver for the conversion from the preleukaemic state to the B-ALL state is exposure to immune stressors, such as infection. Here, we discuss our current understanding of the environmental triggers and genetic predispositions that may lead to B-ALL, highlighting lessons from epidemiology, the clinic and animal models, and identifying priority areas for future research.
Subject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Animals , Carcinogenesis/genetics , Child , Gene-Environment Interaction , Genetic Predisposition to Disease , Humans , Infections/complications , Microbiota/immunology , Models, Biological , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cells, B-Lymphoid/immunology , Precursor Cells, B-Lymphoid/metabolism , Preleukemia/etiology , Preleukemia/genetics , Preleukemia/immunology , Risk Factors , Tumor Microenvironment/genetics , Tumor Microenvironment/immunologySubject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Clonal Hematopoiesis , Leukemia, Myeloid, Acute/chemically induced , Myelodysplastic Syndromes/chemically induced , Neoplasms, Second Primary/chemically induced , Neuroblastoma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Clonal Evolution , Combined Modality Therapy , Female , Hematopoietic Stem Cell Transplantation , Humans , Mutation , Myeloablative Agonists/adverse effects , Myeloablative Agonists/therapeutic use , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/physiopathology , Neuroblastoma/drug therapy , Preleukemia/chemically induced , Preleukemia/genetics , Preleukemia/physiopathology , Transplantation Conditioning/adverse effects , Transplantation, AutologousABSTRACT
Haematopoietic stem and progenitor cells (HSPCs) are defined as unspecialized cells that give rise to more differentiated cells. In a similar way, leukaemic stem and progenitor cells (LSPCs) are defined as unspecialized leukaemic cells, which can give rise to more differentiated cells. Leukaemic cells carry leukaemic mutations/variants and have clear differentiation abnormalities. Pre-leukaemic HSPCs (PreL-HSPCs) carry pre-leukaemic mutations/variants (pLMs) and are capable of producing mature functional cells, which will carry the same variants. Under the roof of LSPCs, one can find a broad range of cell types genetic and disease phenotypes. Present-day knowledge suggests that this phenotypic heterogeneity is the result of interactions between the cell of origin, the genetic background and the microenvironment background. The combination of these attributes will define the LSPC phenotype, frequency, differentiation capacity and evolutionary trajectory. Importantly, as LSPCs are leukaemia-initiating cells that sustain clinical remission and are the source of relapse, an improved understanding of LSPCs phenotype would offer better clinical opportunities for the treatment and hopefully prevention of human leukaemia. The current review will focus on LSPCs attributes in the context of human haematologic malignancies.
Subject(s)
Hematopoietic Stem Cells/pathology , Leukemia/pathology , Preleukemia/pathology , Biomarkers, Tumor , Bone Marrow/pathology , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Genetic Variation , Hematopoiesis , Humans , Leukemia/genetics , Leukemia/metabolism , Mutation , Phenotype , Preleukemia/genetics , Preleukemia/metabolism , Tumor MicroenvironmentSubject(s)
Biomarkers, Tumor/genetics , Databases, Factual , Leukemia, Myeloid, Acute/pathology , Mutation , Myelodysplastic Syndromes/pathology , Preleukemia/pathology , Adult , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/genetics , Male , Myelodysplastic Syndromes/genetics , Preleukemia/genetics , Prognosis , Sex FactorsABSTRACT
Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, including abnormal histone and DNA methylation, have been implicated in the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether and how IDH mutations themselves affect hematopoiesis. Here, we show that IDH1-mutant mice develop myeloid dysplasia in that these animals exhibit anemia, ineffective erythropoiesis, and increased immature progenitors and erythroblasts. In erythroid cells of these mice, D-2-hydroxyglutarate, an aberrant metabolite produced by the mutant IDH1 enzyme, inhibits oxoglutarate dehydrogenase activity and diminishes succinyl-coenzyme A (CoA) production. This succinyl-CoA deficiency attenuates heme biosynthesis in IDH1-mutant hematopoietic cells, thus blocking erythroid differentiation at the late erythroblast stage and the erythroid commitment of hematopoietic stem cells, while the exogenous succinyl-CoA or 5-ALA rescues erythropoiesis in IDH1-mutant erythroid cells. Heme deficiency also impairs heme oxygenase-1 expression, which reduces levels of important heme catabolites such as biliverdin and bilirubin. These deficits result in accumulation of excessive reactive oxygen species that induce the cell death of IDH1-mutant erythroid cells. Our results clearly show the essential role of IDH1 in normal erythropoiesis and describe how its mutation leads to myeloid disorders. These data thus have important implications for the devising of new treatments for IDH-mutant tumors.
Subject(s)
Erythropoiesis/genetics , Hematopoietic Stem Cells/metabolism , Heme/biosynthesis , Isocitrate Dehydrogenase/genetics , Mutation, Missense , Point Mutation , Preleukemia/genetics , Acyl Coenzyme A/biosynthesis , Acyl Coenzyme A/deficiency , Anemia/genetics , Animals , Bone Marrow/pathology , Erythroblasts/metabolism , Gene Knock-In Techniques , Glutarates/metabolism , Heme/deficiency , Heme Oxygenase-1/metabolism , Isocitrate Dehydrogenase/physiology , Ketoglutarate Dehydrogenase Complex/antagonists & inhibitors , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Myeloid Cells/pathology , Myelopoiesis/genetics , Preleukemia/metabolism , Preleukemia/pathology , Reactive Oxygen Species/metabolism , Recombinant Proteins/metabolism , Splenomegaly/etiology , Thrombocytopenia/geneticsABSTRACT
Patients with the pre-leukemia bone marrow failure syndrome called severe congenital neutropenia (CN) have an approximately 15% risk of developing acute myeloid leukemia (AML; called here CN/AML). Most CN/AML patients co-acquire CSF3R and RUNX1 mutations, which play cooperative roles in the development of AML. To establish an in vitro model of leukemogenesis, we utilized bone marrow lin- cells from transgenic C57BL/6-d715 Csf3r mice expressing a CN patient-mimicking truncated CSF3R mutation. We transduced these cells with vectors encoding RUNX1 wild type (WT) or RUNX1 mutant proteins carrying the R139G or R174L mutations. Cells transduced with these RUNX1 mutants showed diminished in vitro myeloid differentiation and elevated replating capacity, compared with those expressing WT RUNX1. mRNA expression analysis showed that cells transduced with the RUNX1 mutants exhibited hyperactivation of inflammatory signaling and innate immunity pathways, including IL-6, TLR, NF-kappaB, IFN, and TREM1 signaling. These data suggest that the expression of mutated RUNX1 in a CSF3R-mutated background may activate the pro-inflammatory cell state and inhibit myeloid differentiation.
Subject(s)
Congenital Bone Marrow Failure Syndromes/genetics , Core Binding Factor Alpha 2 Subunit/genetics , Hematopoietic Stem Cells/pathology , Myeloid Cells/pathology , Myelopoiesis/genetics , Neutropenia/congenital , Preleukemia/genetics , Receptors, Colony-Stimulating Factor/genetics , Animals , Cell Division , Colony-Forming Units Assay , Congenital Bone Marrow Failure Syndromes/pathology , Core Binding Factor Alpha 2 Subunit/physiology , Gene Expression Profiling , Immunity, Innate , Inflammation , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neutropenia/genetics , Neutropenia/pathology , Preleukemia/pathology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Colony-Stimulating Factor/physiology , Recombinant Proteins/genetics , Specific Pathogen-Free OrganismsABSTRACT
There is clear evidence that ionizing radiation (IR) causes leukemia. For many types of leukemia, the preleukemic fusion genes (PFG), as consequences of DNA damage and chromosomal translocations, occur in hematopoietic stem and progenitor cells (HSPC) in utero and could be detected in umbilical cord blood (UCB) of newborns. However, relatively limited information is available about radiation-induced apoptosis, DNA damage and PFG formation in human HSPC. In this study we revealed that CD34+ HSPC compared to lymphocytes: (i) are extremely radio-resistant showing delayed time kinetics of apoptosis, (ii) accumulate lower level of endogenous DNA damage/early apoptotic γH2AX pan-stained cells, (iii) have higher level of radiation-induced 53BP1 and γH2AX/53BP1 co-localized DNA double stranded breaks, and (iv) after low dose of IR may form very low level of BCR-ABL PFG. Within CD34+ HSPC we identified CD34+CD38+ progenitor cells as a highly apoptosis-resistant population, while CD34+CD38- hematopoietic stem/multipotent progenitor cells (HSC/MPP) as a population very sensitive to radiation-induced apoptosis. Our study provides critical insights into how human HSPC respond to IR in the context of DNA damage, apoptosis and PFG.
Subject(s)
DNA Breaks, Double-Stranded/radiation effects , Fetal Blood/radiation effects , Gene Fusion/radiation effects , Hematopoietic Stem Cells/radiation effects , Leukemia/genetics , Antigens, CD34/metabolism , Apoptosis/radiation effects , DNA Repair/genetics , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/radiation effects , Gene Fusion/genetics , Histones/genetics , Histones/metabolism , Humans , Infant, Newborn , Lymphocytes/radiation effects , Preleukemia/genetics , Radiation, Ionizing , Tumor Suppressor p53-Binding Protein 1/genetics , Tumor Suppressor p53-Binding Protein 1/metabolismABSTRACT
Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated BDH2mRNA expression in BM is observed in MDS patients (n = 187 vs. 43, normal BM; P = 0.009), and this is related to ferritin levels. Patients with higher BDH2 expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression; P = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years; P = 0.024), as do patients with a ferritin level ≥350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS.
Subject(s)
Bone Marrow/pathology , Gene Expression Regulation/genetics , Hydroxybutyrate Dehydrogenase/physiology , Leukemia, Myeloid, Acute/enzymology , Myelodysplastic Syndromes/enzymology , Preleukemia/enzymology , Adult , Aged , Aged, 80 and over , Apoptosis/genetics , Bone Marrow/metabolism , Cell Cycle Checkpoints/genetics , Cell Differentiation/genetics , Female , Ferritins/blood , Gene Expression Regulation, Leukemic , Humans , Hydroxybutyrate Dehydrogenase/biosynthesis , Hydroxybutyrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Lipocalin-2/biosynthesis , Lipocalin-2/genetics , Male , Middle Aged , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/blood , Neoplasm Proteins/genetics , Neoplasm Proteins/physiology , Preleukemia/genetics , Preleukemia/pathology , Prognosis , Progression-Free Survival , RNA Interference , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , RNA, Small Interfering/genetics , THP-1 Cells , Young AdultABSTRACT
The initiating mutations that contribute to cancer development are sometimes present in premalignant cells. Whether therapies targeting these mutations can eradicate premalignant cells is unclear. Acute myeloid leukemia (AML) is an attractive system for investigating the effect of preventative treatment because this disease is often preceded by a premalignant state (clonal hematopoiesis or myelodysplastic syndrome). In Npm1c/Dnmt3a mutant knock-in mice, a model of AML development, leukemia is preceded by a period of extended myeloid progenitor cell proliferation and self-renewal. We found that this self-renewal can be reversed by oral administration of a small molecule (VTP-50469) that targets the MLL1-Menin chromatin complex. These preclinical results support the hypothesis that individuals at high risk of developing AML might benefit from targeted epigenetic therapy in a preventative setting.
Subject(s)
Genetic Therapy/methods , Leukemia, Experimental/prevention & control , Leukemia, Myeloid, Acute/prevention & control , Nuclear Proteins/genetics , Preleukemia/therapy , Animals , Chromatin/metabolism , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methyltransferase 3A , Gene Knock-In Techniques , Histone-Lysine N-Methyltransferase/metabolism , Leukemia, Experimental/genetics , Leukemia, Myeloid, Acute/genetics , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Mutation , Myeloid Progenitor Cells/pathology , Myeloid-Lymphoid Leukemia Protein/metabolism , Nucleophosmin , Preleukemia/genetics , Preleukemia/pathology , Proto-Oncogene Proteins/metabolismABSTRACT
Myeloid neoplasms including myelodysplastic syndromes and acute myeloid leukemia (AML) originate from hematopoietic stem cells through sequential acquisition of genetic and epigenetic alterations that ultimately cause the disease-specific phenotype of impaired differentiation and increased proliferation. It has become clear that preleukemic clonal hematopoiesis (CH), characterized by an expansion of stem and progenitor cells that carry somatic mutations but are still capable of normal differentiation, can precede the development of clinically overt myeloid neoplasia by many years. CH commonly develops in the aging hematopoietic system, yet progression to myelodysplasia or AML is rare. The discovery that myeloid neoplasms frequently develop from premalignant precursor conditions that are detectable in many healthy individuals has important consequences for the diagnosis, and potentially for the treatment of these disorders. In this review, we summarize the current knowledge on CH as a precursor of myeloid cancers and the implications of CH-related gene mutations in the diagnostic workup of patients with suspected myelodysplastic syndrome. We will discuss the risk of progression associated with CH in healthy persons and in patients undergoing chemotherapy for a non-hematologic cancer, and the significance of CH in autologous and allogeneic stem cell transplantation. Finally, we will review the significance of preleukemic clones in AML and their persistence in patients who achieve a remission after chemotherapeutic treatment.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Myelodysplastic Syndromes/genetics , Myeloproliferative Disorders/pathology , Clonal Evolution , Clone Cells/pathology , Hematopoiesis/genetics , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells , Humans , Leukemia, Myeloid, Acute/pathology , Myelodysplastic Syndromes/pathology , Myeloproliferative Disorders/genetics , Preleukemia/genetics , Preleukemia/pathologyABSTRACT
The bone marrow microenvironment, also known as the bone marrow niche, is a complex network of cell types and acellular factors that supports normal hematopoiesis. For many years, leukemia was believed to be caused by a series of genetic hits to hematopoietic stem and progenitor cells, which transform them to preleukemic, and eventually to leukemic, cells. Recent discoveries suggest that genetic alterations in bone marrow niche cells, particularly in osteogenic cells, may also cause myeloid leukemia in mouse models. The osteogenic niche, which consists of osteoprogenitors, preosteoblasts, mature osteoblasts, osteocytes and osteoclasts, has been shown to play a critical role in the maintenance and expansion of hematopoietic stem and progenitor cells as well as in their oncogenic transformation into leukemia stem/initiating cells. We have recently shown that acute myeloid leukemia cells induce osteogenic differentiation in mesenchymal stromal cells to gain a growth advantage. In this review, we discuss the role of the osteogenic niche in the maintenance of hematopoietic stem and progenitor cells, as well as in their transformation into leukemia cells. We also discuss the signaling pathways that regulate osteogenic niche-hematopoietic stem and progenitor cells or osteogenic niche-leukemic stem/initiating cell interactions in the bone marrow, together with novel approaches for therapeutically targeting these interactions.
Subject(s)
Hematopoiesis/genetics , Hematopoietic Stem Cells/metabolism , Leukemia/genetics , Osteogenesis/genetics , Preleukemia/genetics , Stem Cell Niche , Animals , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation , Humans , Signal Transduction/geneticsABSTRACT
Recent advances in next-generation sequencing have identified novel mutations and revealed complex genetic architectures in human hematological malignancies. Moving forward, new methods to quickly generate animal models that recapitulate the complex genetics of human hematological disorders are needed to transform the genetic information to new therapies. Here, we used a ribonucleoprotein-based CRISPR/Cas9 system to model human clonal hematopoiesis of indeterminate potential and acute myeloid leukemia (AML). We edited multiple genes recurrently mutated in hematological disorders, including those encoding epigenetic regulators, transcriptional regulators, and signaling components in murine hematopoietic stem/progenitor cells. Tracking the clonal dynamics by sequencing the indels induced by CRISPR/Cas9 revealed clonal expansion in some recipient mice that progressed to AML initiated by leukemia-initiating cells. Our results establish that the CRISPR/Cas9-mediated multiplex mutagenesis can be used to engineer a variety of murine models of hematological malignancies with complex genetic architectures seen in human disease.