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Offprint requests to: Toshio Kitamura, MD, PhD, Division of Cellular Therapy, The Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 1088639, Japan
The epigenetic regulator ASXL1 is frequently mutated in CH and in a wide range of myeloid neoplasms.
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ASXL1 mutations could contribute to pathogenesis through loss-of-function, dominant-negative, or gain-of-function mutations.
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Aberrant histone modifications, signal transduction, and autoimmunity may be responsible for ASXL1 mutation-induced CH.
Recent advances in DNA sequencing technologies have enhanced our knowledge about several diseases. Coupled with easy accessibility to blood samples, hematology plays a leading role in understanding the process of carcinogenesis. Clonal hematopoiesis (CH) with somatic mutations is observed in at least 10% of people over 65 years of age, without apparent hematologic disorders. CH is associated with increased risk of hematologic malignancies, which is indicative of a pre-malignant condition. Therefore, a better understanding of CH will help elucidate the mechanism of multi-step tumorigenesis in the hematopoietic system. Somatic mutations of ASXL1 are frequently detected in CH and myeloid malignancies. Although ASXL1 does not have any catalytic activity, it is involved in multiple histone modifications including H3K4me3, H3K27me3, and H2AK119Ub, suggesting its function as a scaffolding protein. Most ASXL1 mutations detected in CH and myeloid malignancies are frameshift or nonsense mutations of the last exon, generating a C-terminally truncated protein. Deletion of Asxl1 or expression of mutant ASXL1 in mice alters histone modifications and facilitates aberrant gene expression, resulting in myeloid transformation. On the contrary, these mice exhibit impaired functioning of hematopoietic stem cells (HSCs), suggesting the negative effects of ASXL1 mutations on stem cell function. Thus, how ASXL1 mutations induce a clonal advantage of hematopoietic cells and subsequent CH development has not been elucidated. Here, we have reviewed the current literature that enhances our understanding of ASXL1, including its mutational landscape, function, and involvement of its mutation in pathogenesis of CH and myeloid malignancies. Finally, we discuss the potential causes of CH harboring ASXL1 mutations with our latest knowledge.
Mutational landscape of ASXL1 in CH and myeloid malignancies
The presence of clonal hematopoiesis (CH) was first recognized around 50 years ago [
]. In females, one of the two X chromosomes is randomly inactivated; this is termed X-inactivation or lyonization. The occurrence of a biased X-inactivation, toward either the paternal or maternal X chromosome, is called X-inactivation skewing (XIS). XIS has been used to analyze clonality since the 1960s. In 1994, Fey et al. [
] reported that XIS occurred in the peripheral blood of healthy women and was more prevalent in elderly women (75–96 years old) than in younger women (20–58 years old). Busque et al. [
] suggested that increased XIS in healthy individuals undergoing aging represents clonal expansion of hematopoietic cells, that is, CH. Considering the increased incidence of hematologic malignancies during aging, they also predicted that CH could be a premalignant state resulting from somatic mutations that confer a clonal advantage on hematopoietic stem cells (HSCs).
Advances in next-generation sequence technologies have enabled us to detect somatic mutation events with higher sensitivity. In 2014, three groups simultaneously reported that clonal expansion of blood cells harboring somatic mutations was present in about 10% of healthy individuals older than 65 years of age without abnormality in their hematologic parameters [
]. These studies also identified somatic mutations in epigenetic regulators, including DNMT3A, ASXL1, and TET2, to be among the most frequently mutated genes in individuals with CH. Given that genes mutated in CH are similar to those in myeloid malignancies, and that CH is associated with an increased risk of subsequent hematologic malignancies [
] reported that individuals with CH are at an increased risk of developing cardiovascular diseases and atherosclerosis, and mutations in DNMT3A, TET2, ASXL1, and JAK2 were recurrently detected in them. Studies suggest that macrophage-driven inflammatory responses are responsible for the accelerated atherosclerosis seen in these patients [
In addition to CH, somatic mutations in the ASXL1 gene are frequently detected in various types of myeloid malignancies including myelodysplastic syndromes (MDS, 14%−23%) [
]. Mutations in ASXL1 are related to poor prognosis of these diseases. It has been found that the majority of patients with ASXL1 mutations have other mutations at the same time. Mutations in ASXL1 co-exist with those in epigenetic factors (IDH2, EZH2), splicing factors (SRSF2, U2AF1), signal transduction molecules (JAK2, NRAS, SETBP1), transcription factor (RUNX1), and components of cohesion complex (STAG2) [
]. As patients with AA sometimes develop MDS or AML, and genes mutated in these diseases seem to be overlapping, it is possible that MDS and AML could develop from the same CH clones as AA in some patients. Taken together, ASXL1 mutations are closely involved with the development of CH and myeloid malignancies, suggesting that they are among the earliest events in the process of malignant transformation.
ASXL1 as an epigenetic regulator
The ASXL1 gene was identified as one of the three human homologues of the Drosophila Asx gene and it functions as an epigenetic regulator [
]. ASXL1 consists of 1,541 amino acid residues, and harbors the ASXH domain in the N-terminal region and the plant homeodomain (PHD) domain in the C-terminal region (Figure 1) [
], suggesting the importance of this domain in epigenetic regulation.
Figure 1Localization of DNMT3A, TET2, and ASXL1 mutations in AML patients. Mutations in DNMT3A and TET2 include missense, nonsense, or frameshift mutations. They tend to spread throughout the genes, except for DNMT3A R882 hotspot mutation. Nonsense or frameshift mutations in the ASXL1 gene are concentrated in N-terminus of the last exon, generating a C-terminally truncated form of ASXL1 (Mutant ASXL1). Each mutation is depicted as a circle (white: frame shift mutation, gray: missense mutation, black: nonsense mutation). Hotspot mutations are indicated in boldface. ASXH=Asx homology; ASXN=Asx N-terminal; Cys-rich=cysteine-rich; DSBH=double stranded β-helix; MTase=methyltransferase; NR box=nuclear receptor co-regulator binding motif; PHD=plant homeodomain; PWWP=proline–tryptophan–tryptophan–proline; ZNF=zinc finger.
In Drosophila, expression of genes required for somitogenesis during the embryonic stage is regulated by both Trithorax group (TrxG) and Polycomb group (PcG) complexes [
]. The TrxG complex trimethylates histone H3 at lysine 4 (H3K4me3), resulting in transcriptional activation. The PcG complex is divided into two groups: Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2). The former ubiquitinates histone H2A at lysine 119 (H2AK119Ub), and the latter trimethylates histone H3 at lysine 27 (H3K27me3). Both modifications repress the expression of the target genes [
The Additional sex combs gene of Drosophila is required for activation and repression of homeotic loci, and interacts specifically with Polycomb and super sex combs.
] reported that ASXL1 bound to components of PRC2 including EZH2 and EED. ASXL1 loss resulted in global exclusion of H3K27me3, implying that ASXL1 cooperated with PRC2 complex to trimethylate H3K27. Scheuermann et al. [
] have shown that ASXL1 and BAP1 form a complex, termed Polycomb repressive de-ubiquitinase (PR-DUB). PR-DUB complex removes monoubiquitin from H2AK119Ub to derepress genes targeted by PRC1. Intriguingly, mutations in components of PRC1 (BCOR and BCORL1) and PRC2 (EZH2, EED, and SUZ12) complexes are recurrently detected in myeloid malignancies, suggesting that ASXL1 mutations induce leukemogenesis via alteration of normal histone modifications. Of note, in patients with ASXL1 mutations, concurrent mutations in EZH2 are frequently detected [
]. We have previously revealed that knockdown of ASXL1 decreases the level of H3K4me3 in human leukemic cells and proposed that the ASXL1–OGT–HCFC1 complex collaborates with MLL5 to trimethylate H3K4 [
]. Although the exact mechanism remains to be fully elucidated, these studies strongly suggest the involvement of ASXL1 in the trimethylation of H3K4. Collectively, ASXL1 is involved in various histone modifications, such as H3K27me3, H2AK119Ub, and H3K4me3, to regulate gene expression, and might function as a scaffold for epigenetic regulators.
Roles of ASXL1 in hematopoiesis
As described earlier, ASXL1 is involved in various histone modifications to maintain proper gene expression. To clarify the role of ASXL1 in normal hematopoiesis and the impact of ASXL1 deficiency on the pathogenesis of myeloid malignancies, Asxl1-deficient mice have been generated by several groups (Table 1) [
] generated an Asxl1 conventional knockout mouse and demonstrated that heterogeneous loss of Asxl1 led to the development of an MDS-like disease. In these mice, Asxl1 loss resulted in impaired function of HSCs associated with pancytopenia and myeloid-biased differentiation. Moreover, Lin−c-kit+ cells in Asxl1 knockout mice decreased global levels of H3K4me3 and H3K27me3. Abdel-Wahab et al. [
] bred Cre-mediated conditional Asxl1 knockout mice with interferon-inducible Mx1-Cre transgenic mice or hematopoietic lineage-specific Vav-Cre transgenic mice. Conditional deletion of Asxl1 in mice resulted in age-dependent leukocytopenia and anemia with dysplasia in the context of impaired differentiation. Asxl1 deficiency caused an increase in HSCs, but impaired self-renewal of HSCs associated with increased apoptosis. Bone marrow transplantation of Asxl1-deficient cells led to the development of lethal MDS-like disease. In these mice, Asxl1 loss resulted in global reduction of H3K27me3, followed by de-repression of posterior HoxA genes and p16INK4a, suggesting a dysfunction of PRC2.
These studies suggest that ASXL1 is indispensable for normal differentiation of blood cells and maintenance of HSC function, presumably through epigenetic regulations including trimethylation of H3K4 and H3K27. Importantly, these knockout mouse models suggest that ASXL1 mutations could cause hematologic malignancies by loss of function.
ASXL1 mutations gain functions
A series of studies using Asxl1 knockout mice closely recapitulate the pathology of human MDS, implying loss of function as a consequence of ASXL1 mutations. Apart from the knockout mouse model, several studies have revealed that the expression of mutant ASXL1 in mice induces the development of MDS-like disease, raising a question about whether the loss of ASXL1 function is necessary and sufficient for the pathogenesis of myeloid malignancies as well as CH.
Here, we summarize mutations in epigenetic regulators including DNMT3A, TET2, and ASXL1 (Figure 1). Mutations of TET2 seem to be dispersed across the coding region, suggesting loss-of-function mutations, which supports the validity of using a knockout mouse as a model for TET2-mutated diseases [
]. DNMT3A mutations are probably mixtures of the frequent missense mutations (R882C/H/S) and dispersed mutations, suggesting gain-of-function and loss-of-function mutations, respectively [
]. On the other hand, most mutations in ASXL1 are frameshift or nonsense mutations in the N-terminal region of the last exon, generating a C-terminally truncated form of ASXL1 lacking PHD domain (hereinafter referred to as mutant ASXL1) [
]. In general, mRNAs containing premature termination codons (PTCs) are degraded by nonsense-mediated mRNA decay (NMD). However, as mutations in ASXL1 are located in the last exon, they are assumed to escape from NMD. In fact, we have found that the C-terminally truncated form of ASXL1 was present in leukemic cell lines by mass spectrometry and western blot analyses [
]. These results suggest that mutations in ASXL1 may result in dominant-negative or gain-of function mutations, and further raise the issue as to whether a knockout mouse that has been conventionally used is appropriate for a disease model of human ASXL1-mutated diseases.
We previously investigated if mutant ASXL1 proteins induce myeloid transformation using a mouse transplantation model [
]. Mice transplanted with bone marrow cells expressing mutant ASXL1 exhibited progressive pancytopenia, multilineage dysplasia after a long latency, and subsequent overt leukemia in some mice, mimicking MDS in humans. We found that mutant ASXL1 caused de-repression of posterior HoxA genes and miR-125a through inhibition of PRC2-mediated H3K27 trimethylation. De-repression of miR-125a decreased the expression of Clec5a in addition to its known target p53 pathway genes, leading to impaired myeloid differentiation. As is the case with the loss-of-function model, these data suggest that mutant ASXL1 inhibits PRC2 function, followed by upregulation of its target genes in a dominant-negative manner, which contributes to the development of myeloid malignancies.
As described above, ASXL1 and BAP1 form a DUB complex to de-ubiquitinate H2AK119Ub. Recently, our group and others have revealed that mutant ASXL1 aberrantly enhances the de-ubiquitinase (DUB) activity of BAP1 and altered gene expression [
]. Mechanistically, BAP1 mono-ubiquitinated and stabilized mutant ASXL1, which in turn enhanced the DUB activity of BAP1. The overactive mutant ASXL1/BAP1 complex aberrantly de-ubiquitinated H2AK119Ub, followed by de-repression of its target genes including posterior HOXA genes and IRF8, leading to leukemic transformation and impaired myeloid differentiation, respectively. These results indicate that mutations in ASXL1 can contribute to myeloid transformation by means of gain of function.
Collectively, ASXL1 mutations can provoke malignant transformation through not merely loss-of-function but also dominant-negative and gain-of-function mechanisms.
Impact of ASXL1 mutations on hematopoiesis in vivo
It is becoming accepted that the mutant ASXL1 protein is involved in the pathogenesis of myeloid malignancies, and a series of studies using mutant ASXL1 knock-in mice has been published by several groups. In this section, we summarize the characterization of these knock-in mouse models (Table 1) [
] generated a constitutive knock-in mouse carrying the mouse Asxl1 G643WfsX12 mutation (corresponding to the human G646WfsX12 mutation) in the endogenous Asxl1 gene. Mutant ASXL1 knock-in mice did not exhibit obvious abnormalities in hematologic parameters and histology. Moreover, they did not develop hematologic malignancies during the observation period of 18 months, indicating that an ASXL1 mutation alone is not sufficient to induce hematologic diseases. In these mice, mutant ASXL1 impaired the long-term repopulation potential of HSCs and slightly disrupted distribution of H3K27me3. Uni et al. [
] also engineered and analyzed mouse Asxl1 G643WfsX12 constitutive knock-in mice. These mice exhibited age-dependent leukocytopenia and thrombocytosis. The number of Lin−Sca1+c-kit+ (LSK) cells decreased along with increased apoptosis in mutant ASXL1 knock-in mice, suggesting a negative impact of mutant ASXL1 on hematopoietic stem and progenitor cells (HSPCs). Unlike a study by Hsu et al. [
] mice developed MDS/MPN-like diseases associated with dysplasia in myeloid lineage 1.5–2 years after birth. They reported that wild-type ASXL1, but not mutant ASXL1, bound to BMI1, a component of PRC1. The levels of H2AK119Ub in the p16Ink4a locus, which is a known target of PRC1, was decreased, leading to de-repression of p16Ink4a in mutant ASXL1-expressing Lin– cells. p16Ink4a loss normalized the number and frequency of Annexin V-positive cells in LSK cells of mutant ASXL1 knock-in mice. These data suggest that mutant ASXL1 disturbs the recruitment of PRC1 to the p16Ink4a locus and induces de-repression of p16Ink4a, resulting in increased apoptosis and a decreased number of HSPCs. We generated a hematopoietic lineage-specific Vav-Cre mutant ASXL1 knock-in mouse harboring a human ASXL1 E635RfsX15 mutation inserted into the Rosa26 locus [
]. Although the mutant mice exhibited impaired erythroid differentiation and age-dependent mild anemia, they did not develop hematologic disorders during the observation period of 70 weeks. Thus, similar to a report from Hsu et al. [
], an ASXL1 mutation alone was insufficient for inducing the development of hematologic malignancies. However, they increased susceptibility of leukemogenesis by co-occurring expression of mutant RUNX1 or viral insertional mutagenesis indicative of a pre-malignant state. Similar to other knock-in mouse models, mutant ASXL1 reduced the number and the function of HSCs. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) analysis using c-kit+ cells revealed global reduction in levels of H2AK119Ub and H3K4me3 in mutant ASXL1 knock-in mice. In particular, levels of H3K4me3 at the loci of erythroid differentiation-related genes, such as Id3, Tjp1 and Sox6, were markedly decreased.
Taken together, these studies suggest that mutant ASXL1 impairs hematopoiesis through dysregulation of epigenetic modifications. The phenotypic differences between mouse models may come from the site of mutations, expression levels, or genetic background (Asxl1 locus-specific knock-in or Rosa26 locus knock-in). In any case, it is likely that a single ASXL1 mutation is not sufficient to induce malignant transformation, raising the possibility that mutant ASXL1 knock-in mice represent a premalignant condition such as CH.
Mechanistic link between ASXL1 mutations and CH
Although precise mechanisms underlying ASXL1 mutation-induced CH remain elusive, previous studies left clues for unraveling this question. Here, we discuss how ASXL1 mutations promote the development of CH considering previous studies on ASXL1 and the general cause of CH. Mutations that confer increased self-renewal, decreased apoptosis, or impaired differentiation could promote a growth advantage for HSCs. Furthermore, both cell-intrinsic and -extrinsic factors, including DNA damage, microenvironmental changes, therapy, and autoimmunity, would act as selective pressures to HSCs (Figure 2). Presumably, HSC clones harboring mutations that confer a growth advantage gradually expand over time in the presence of selective pressures, eventually leading to development of CH.
Figure 2ASXL1 regulates gene expression through histone modifications including H2AK119Ub, H3K4me3, and H3K27me3. Mutant ASXL1 abrogates trimethylation of H3K4 and H3K27. In addition, mutant ASXL1 collaborates with BAP1 to promote de-ubiquitination of H2AK119Ub. These alterations in histone modifications induce aberrant gene expression, which may lead to a fitness advantage. Alternatively, abnormal histone modifications caused by mutant ASXL1 may accelerate “epigenetic drift.” As mutations in ASXL1 are frequently detected in CH with aplastic anemia, autoimmunity could be involved in a clonal selection of the HSC pool. It is possible that mutant ASXL1 augments signal transduction to induce proliferation of the CH clone. ASXL1-MT=mutant ASXL1; ASXL1-WT=wild-type ASXL1.
]. DNA methylation marks play a pivotal role in the regulation of gene expression. It was reported that loss of Dnmt3a in mice increased self-renewal and impaired differentiation of HSCs [
]. These studies suggest that the perturbation of DNA methylation profiles could result in increased self-renewal and differentiation block, leading to a fitness advantage of the HSC clone. Similarly, ASXL1 mutations were also expected to increase the self-renewal of HSCs. However, previous studies reported impaired function of HSCs in Asxl1-deficient or mutant ASXL1-expressing mice [
]. How this discrepancy occurs is yet to be delineated, and is discussed in the next section. It is likely that ASXL1 mutations provoke differentiation block and aberrant proliferation of HSCs through disruption of epigenetic modifications (e.g., H2AK119Ub, H3K4me3, H3K27me3) [
] reported that aged HSCs exhibited hypermethylation in genes associated with differentiation and hypomethylation in genes associated with maintenance of stem cell function. Single-cell analyses of HSCs revealed that chromatin modifications became more heterogeneous between individuals and single cells over time [
]. It is possible that epigenetic drift causes continuous alteration of the epigenomic modifications followed by changes in self-renewal and differentiation potential of HSCs. As epigenetic modifications can be transmitted to daughter cells, they could be important contributors to clonal selection in addition to gene mutations. Mutations in epigenetic regulators including ASXL1 could cause diverse changes in epigenetics to accelerate epigenetic abnormality, which may confer a growth advantage to HSCs.
DNA damage response
It has been previously reported that chemotherapy and radiation therapy act as exogenous selective pressures to contribute to the development of CH [
]. Mutations in DNA damage response (DDR)-related genes, including TP53 and PPM1D, are recurrently found at high frequencies in patients with therapy-related AML (tAML) and MDS (tMDS) [
Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis.
] revealed that after chemotherapy and radiation therapy among cancer patients, the frequency of such individuals with CH harboring TP53 or PPM1D mutations significantly increased. Moreover, Hsu et al. [
] reported that PPM1D mutant-expressing cells are more resistant to cytotoxic chemotherapy compared with wild-type cells. These data suggest that cells bearing TP53 or PPM1D mutations tend to acquire a fitness advantage to develop CH under the exposure of external genotoxic stresses. On the other hand, it is unlikely that ASXL1 mutations confer tolerance against genotoxic stresses on hematopoietic cells like TP53 and PPM1D mutations, as they appear to be unrelated to the prior therapy given [
]. Consistent with this, HSCs expressing mutant ASXL1 exhibit increased susceptibility to ionizing radiation in our knock-in mouse model (unpublished data).
Oncogene
Mutations in classic oncogenic genes involved in signal transduction are not common in CH. In this group, the most frequently detected mutation is Janus kinase 2 (JAK2) V617F substitution [
] found that Asxl1 forms a ternary complex with Akt1 and p27 in mouse embryonic fibroblasts (MEFs). They reported that Akt was not phosphorylated after IGF-1 stimulation in Asxl1-deficient MEFs, suggesting a potential role of ASXL1 in the PI3K/AKT signaling pathway. It is possible that ASXL1 mutations may alter the activity of proliferation-driving signal transduction pathways to induce clonal advantage in hematopoietic cells.
Autoimmunity
Autoimmunity can provide a selective pressure in HSCs to yield clonal selection in the hematopoietic system. AA is considered to be an autoimmune disease, in which autoreactive cytotoxic T cells attack HSCs and eventually lead to bone marrow failure [
]. It should be noted that ASXL1 mutations are among the most frequently detected events in AA, raising the possibility that they affect T-cell functions or alter sensitivity of HSCs in response to autoimmunity. At present, the reason why ASXL1 is frequently mutated in AA is largely unknown. Future study focused on the multilineage interaction, especially HSCs with immune cells, can elucidate the pathogenesis of AA with ASXL1 mutations as well as mutant ASXL1-induced CH.
Mutant ASXL1 knock-in mouse as a model for CH
As described earlier, mutant ASXL1 has a negative impact on HSC function [
]. Thus, it is likely that the mechanisms underlying the development of CH induced by ASXL1 mutations are distinct from those of DNMT3A and TET2 mutations. To address this discrepancy, we examined the effect of mutant ASXL1 on physiological aging of HSCs by using our knock-in mouse model. Although mutant ASXL1 induces a competitive growth disadvantage in transplanted HSCs, HSCs expressing mutant ASXL1 markedly increased over time with no symptoms of hematologic malignancies in Vav-Cre mutant ASXL1 knock-in mice (unpublished data). This model, however, does not accurately reflect human CH because most HSCs express mutant ASXL1. Therefore, there is a need to assess whether a small population of cells expressing mutant ASXL1 acquire a competitive advantage in native hematopoiesis without transplantation. Collectively, our data suggest that the mutant ASXL1 knock-in mouse is useful for elucidating the pathogenesis of ASXL1 mutation-induced CH. Future research would reveal the precise mechanism underlying CH with ASXL1 mutations, which is expected to help the development of therapeutic interventions against CH.
Concluding remarks
ASXL1 is one of the most frequently mutated genes in CH, and its mutations are associated with poor prognosis in myeloid malignancies [
]. Therefore, elucidating the mechanism by which ASXL1 mutations induce CH and subsequent MDS or AML would help prevent the development of hematologic malignancies.
With the help of advanced DNA sequencing technologies, we delineated a catalogue of mutations in hematologic malignancies. Since then, several studies have revealed how these mutations contribute to the pathogenesis. Nevertheless, we cannot completely overcome these diseases at present. At the same time, much effort has been devoted to understanding their mutational history as far back as the preclinical stage, revealing the complex and dynamic changes of clones in the process of disease progression [
], suggesting that CH is a natural effect of aging on the hematopoietic system. So, when, why, and what clones with mutations evolve from CH into malignancy? Is there a clear distinction between CH and subsequent malignant transformation? To fully elucidate this problem, we will need to integratedly analyze multiple layers, including mutation, histone modifications, and gene expression, at a single-cell level and link them to clinical findings over time.
Apart from CH, recent reports have revealed that normal tissues also accumulate somatic mutations with age, which may confer a selective advantage [
]. The reason for this discrepancy remains elusive. A better understanding of CH and subsequent hematologic malignancies would unveil what this difference means and further help us understand the basic principle of a clonal evolution.
Conflict of interest disclosure
The authors declare no conflicts of interest, financial or otherwise.
Acknowledgments
Many thanks to all lab members and our collaborators.
References
Oni SB
Osunkoya BO
L L
Paroxysmal nocturnal hemoglobinuria: evidence for monoclonal origin of abnormal red cells.
The Additional sex combs gene of Drosophila is required for activation and repression of homeotic loci, and interacts specifically with Polycomb and super sex combs.
Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis.
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