MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks.

BACKGROUND: Patients with deleterious variants in MYSM1 have an immune deficiency characterized by B-cell lymphopenia, hypogammaglobulinemia, and increased radiosensitivity. MYSM1 is a histone deubiquitinase with established activity in regulating gene expression. MYSM1 also localizes to sites of DNA injury but its function in cellular responses to DNA breaks has not been elucidated. OBJECTIVES: This study sought to determine the activity of MYSM1 in regulating DNA damage responses (DDRs) to DNA double-stranded breaks (DSBs) generated during immunoglobulin receptor gene (Ig) recombination and by ionizing radiation. METHODS: MYSM1-deficient pre- and non-B cells were used to determine the role of MYSM1 in DSB generation, DSB repair, and termination of DDRs. RESULTS: Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression. Radiosensitivity testing in patient's peripheral blood lymphocytes showed constitutive γH2AX, a marker of DNA damage, in B cells in the absence of irradiation, suggesting a role for MYSM1 in response to DSBs generated during Ig recombination. Suppression of MYSM1 in pre-B cells did not alter generation or repair of Ig DSBs. Rather, loss of MYSM1 resulted in persistent DNA damage foci and prolonged DDR signaling. Loss of MYSM1 also led to protracted DDRs in U2OS cells with irradiation induced DSBs. CONCLUSIONS: MYSM1 regulates termination of DNA damage responses but does not function in DNA break generation and repair.

Long-term assessment of haematological recovery following somatic genetic rescue in a MYSM1-deficient patient: Implications for in vivo gene therapy.

MYSM1 deficiency causes inherited bone marrow failure syndrome (IBMFS). We have previously identified an IBMFS patient with a homozygous pathogenic variant in MYSM1 who recovered from cytopenia due to spontaneous correction of one MYSM1 variant in the haematopoietic compartment, an event called somatic genetic rescue (SGR). The study of the genetic and biological aspects of the patient's haematopoietic/lymphopoietic system over a decade after SGR shows that one genetically corrected haematopoietic stem cell (HSC) can restore a healthy and stable haematopoietic system. This supports in vivo gene correction of HSCs as a promising treatment for IBMFS, including MYSM1 deficiency.

Successful allogeneic stem cell transplantation with fludarabine-based reduced intensity conditioning in bone marrow failure syndrome 4.

BACKGROUND: Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a histone H2A deubiquitinase, has been discovered as one of the transcriptional regulators, and regulates the expression of specific transcription factors, which are essential for immunohematology development. Mutation in MYSM1 in humans leads to a rare autosomal recessive disease that has recently been known as inherited bone marrow failure syndrome 4 (BMFS4) associated with congenital bone marrow failure, immunodeficiency, and developmental aberrations. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for immunohematology defects. METHODS: In this paper, we report a pediatric patient with BMFS4 who suffered from pancytopenia and immunodeficiency affecting B cells and was successfully treated with HSCT from an HLA-identical father at 6 years old of age. Fludarabine-based reduced intensity conditioning was used and resulted in full donor chimerism. RESULTS: Acute graft versus host disease (GVHD) grade II involving skin and gastrointestinal tract was observed, which was controlled with prednisolone. CONCLUSION: She achieved B-cell recovery, and no blood or platelet transfusion was reported 1 year after HSCT.

Interaction of Deubiquitinase 2A-DUB/MYSM1 with DNA Repair and Replication Factors.

The deubiquitination of histone H2A on lysine 119 by 2A-DUB/MYSM1, BAP1, USP16, and other enzymes is required for key cellular processes, including transcriptional activation, apoptosis, and cell cycle control, during normal hematopoiesis and tissue development, and in tumor cells. Based on our finding that MYSM1 colocalizes with γH2AX foci in human peripheral blood mononuclear cells, leukemia cells, and melanoma cells upon induction of DNA double-strand breaks with topoisomerase inhibitor etoposide, we applied a mass spectrometry-based proteomics approach to identify novel 2A-DUB/MYSM1 interaction partners in DNA-damage responses. Differential display of MYSM1 binding proteins significantly enriched after exposure of 293T cells to etoposide revealed an interacting network of proteins involved in DNA damage and replication, including factors associated with poor melanoma outcome. In the context of increased DNA-damage in a variety of cell types in Mysm1-deficient mice, in bone marrow cells upon aging and in UV-exposed Mysm1-deficient skin, our current mass spectrometry data provide additional evidence for an interaction between MYSM1 and key DNA replication and repair factors, and indicate a potential function of 2A-DUB/MYSM1 in DNA repair processes.

Mysm1 epigenetically regulates the immunomodulatory function of adipose-derived stem cells in part by targeting miR-150.

Adipose-derived stem cells (ASCs) are highly attractive for cell-based therapies in tissue repair and regeneration because they have multilineage differentiation capacity and are immunosuppressive. However, the detailed epigenetic mechanisms of their immunoregulatory capacity are not fully defined. In this study, we found that Mysm1 was induced in ASCs treated with inflammatory cytokines. Adipose-derived stem cells with Mysm1 knockdown exhibited attenuated immunosuppressive capacity, evidenced by less inhibition of T cell proliferation, more pro-inflammatory factor secretion and less nitric oxide (NO) production in vitro. Mysm1-deficient ASCs exacerbated inflammatory bowel diseases but inhibited tumour growth in vivo. Mysm1-deficient ASCs also showed depressed miR-150 expression. When transduced with Mysm1 overexpression lentivirus, ASCs exhibited enhanced miR-150 expression. Furthermore, Mysm1-deficient cells transduced with lentivirus containing miR-150 mimics produced less pro-inflammatory factors and more NO. Our study reveals a new role of Mysm1 in regulating the immunomodulatory activities of ASCs by targeting miR-150. These novel insights into the mechanisms through which ASCs regulate immune reactions may lead to better clinical utility of these cells.

Neutrophilic Panniculitis in a child with MYSM1 deficiency.

Neutrophilic panniculitis (NP) with myelodysplasia has been described in adults but not in children. We report a case of NP associated with myelodysplasia in a child with MYSM1 deficiency, a newly described syndrome with primary immunodeficiency (PI), bone marrow failure, and developmental aberrations.

Deubiquitinase Mysm1 regulates macrophage survival and polarization.

Macrophages play pivotal roles in innate and adaptive immune response, tissue homeostasis and cancer development. Their development and heterogeneity are tightly controlled by epigenetic program and transcription factors. Deubiquitinase Mysm1 plays crucial roles in regulating stem cell maintenance and immune cell development. Here we show that Mysm1 expression is up regulated during bone marrow macrophage development. Mysm1 deficient cells exhibit accelerating proliferation with more cells going to S phase and higher cyclin D1, cyclin D2 and c-Myc expression. However, compared to WT counterparts, more cell death is also detected in Mysm1 deficient cells no matter M-CSF deprived or not. In LPS-condition medium, Mysm1-/- macrophages show more pro-inflammatory factors IL-1ß, TNFα and iNOS production. In addition, much higher expression of surface marker CD86 is detected in Mysm1-/- macrophages. In vivo tumor model data demonstrate that in contrast to WT macrophages promoting tumor growth, Mysm1-/- macrophages inhibit tumor growth, showing the properties of M1 macrophages. Collectively, these data indicate that Mysm1 is essential for macrophage survival and plays an important role in macrophage polarization and might be a target for cell therapy.

2A-DUB/Mysm1 Regulates Epidermal Development in Part by Suppressing p53-Mediated Programs.

Development and homeostasis of the epidermis are governed by a complex network of sequence-specific transcription factors and epigenetic modifiers cooperatively regulating the subtle balance of progenitor cell self-renewal and terminal differentiation. To investigate the role of histone H2A deubiquitinase 2A-DUB/Mysm1 in the skin, we systematically analyzed expression, developmental functions, and potential interactions of this epigenetic regulator using Mysm1-deficient mice and skin-derived epidermal cells. Morphologically, skin of newborn and young adult Mysm1-deficient mice was atrophic with reduced thickness and cellularity of epidermis, dermis, and subcutis, in context with altered barrier function. Skin atrophy correlated with reduced proliferation rates in Mysm1-/- epidermis and hair follicles, and increased apoptosis compared with wild-type controls, along with increases in DNA-damage marker γH2AX. In accordance with diminished α6-Integrinhigh+CD34⁺ epidermal stem cells, reduced colony formation of Mysm1-/- epidermal progenitors was detectable in vitro. On the molecular level, we identified p53 as potential mediator of the defective Mysm1-deficient epidermal compartment, resulting in increased pro-apoptotic and anti-proliferative gene expression. In Mysm1-/-p53-/- double-deficient mice, significant recovery of skin atrophy was observed. Functional properties of Mysm1-/- developing epidermis were assessed by quantifying the transepidermal water loss. In summary, this investigation uncovers a role for 2A-DUB/Mysm1 in suppression of p53-mediated inhibitory programs during epidermal development.

An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation.

BACKGROUND: Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities. OBJECTIVES: We sought to characterize the underlying genetic cause of this syndrome. METHODS: We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. RESULTS: Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell. CONCLUSIONS: We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency.

MYSM-1 suppresses migration and invasion in renal carcinoma through inhibiting epithelial-mesenchymal transition.

Renal cell carcinoma (RCC) is the most common malignant renal tumor and is prone to metastasis. However, the molecular variation and mechanism underlying renal cell carcinoma metastasis remains largely unknown. In our previous study, it was found that MYSM-1 was significantly downregulated in renal cell carcinoma tissues as compared with normal renal tissues without metastasis, using proteomics approach. Therefore, we hypothesized that MYSM-1 may suppress the metastasis of renal cell carcinoma in light of paucity of data regarding MYSM-1 in the cancers. In the present study, to confirm the expression status of MYSM-1 in renal cell carcinoma, immunohistochemistry with renal carcinoma tissue microarray was performed. It was shown that MYSM-1 was remarkably decreased in renal carcinoma tissues compared with paired normal control tissues; and that low expression of MYSM-1 was significantly associated with poor overall prognosis and metastasis. To investigate the biological roles of MYSM-1 in vitro in renal carcinoma cell lines, both knockdown using siRNA and over-expression were carried out. It was found that MYSM-1 could suppress the proliferation, migration, and invasion of renal carcinoma cells. In addition, we found that MYSM-1 could inhibit the epithelial-mesenchymal transition. Together, our results demonstrate that MYSM-1 could suppress the metastasis of renal carcinoma cells may be through inhibiting the epithelial-mesenchymal transition (EMT) process.

MYSM1 acts as a novel co-activator of ERα to confer antiestrogen resistance in breast cancer.

Endocrine resistance is a crucial challenge in estrogen receptor alpha (ERα)-positive breast cancer (BCa). Aberrant alteration in modulation of E2/ERα signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Herein, we demonstrate that MYSM1 as a deubiquitinase participates in modulating ERα action via histone and non-histone deubiquitination. MYSM1 is involved in maintenance of ERα stability via ERα deubiquitination. MYSM1 regulates relevant histone modifications on cis regulatory elements of ERα-regulated genes, facilitating chromatin decondensation. MYSM1 is highly expressed in clinical BCa samples. MYSM1 depletion attenuates BCa-derived cell growth in xenograft models and increases the sensitivity of antiestrogen agents in BCa cells. A virtual screen shows that the small molecule Imatinib could potentially interact with catalytic MPN domain of MYSM1 to inhibit BCa cell growth via MYSM1-ERα axis. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ERα action and provide a potential therapeutic target for endocrine resistance in BCa.

Genetic and Pharmacological Inhibition of Astrocytic Mysm1 Alleviates Depressive-Like Disorders by Promoting ATP Production.

Major depressive disorder (MDD) is a leading cause of disability worldwide. A comprehensive understanding of the molecular mechanisms of this disorder is critical for the therapy of MDD. In this study, it is observed that deubiquitinase Mysm1 is induced in the brain tissues from patients with major depression and from mice with depressive behaviors. The genetic silencing of astrocytic Mysm1 induced an antidepressant-like effect and alleviated the osteoporosis of depressive mice. Furthermore, it is found that Mysm1 knockdown led to increased ATP production and the activation of p53 and AMP-activated protein kinase (AMPK). Pifithrin α (PFT α) and Compound C, antagonists of p53 and AMPK, respectively, repressed ATP production and reversed the antidepressant effect of Mysm1 knockdown. Moreover, the pharmacological inhibition of astrocytic Mysm1 by aspirin relieved depressive-like behaviors in mice. The study reveals, for the first time, the important function of Mysm1 in the brain, highlighting astrocytic Mysm1 as a potential risk factor for depression and as a valuable target for drug discovery to treat depression.

MYSM1 inhibits human colorectal cancer tumorigenesis by activating miR-200 family members/CDH1 and blocking PI3K/AKT signaling.

BACKGROUND: Histone epigenetic modification disorder is an important predisposing factor for the occurrence and development of many cancers, including colorectal cancer (CRC). The role of MYSM1, a metalloprotease that deubiquitinates monoubiquitinated histone H2A, in colorectal cancer was identified to evaluate its potential clinical application value. METHODS: MYSM1 expression levels in CRC cell lines and tumor tissues were detected, and their associations with patient survival rate and clinical stage were analyzed using databases and tissue microarrays. Gain- and loss-of-function studies were performed to identify the roles of MYSM1 in CRC cell proliferation, apoptosis, cell cycle progression, epithelial-mesenchymal transition (EMT) and metastasis in vitro and in vivo. ChIP, rescue assays and signal pathway verification were conducted for mechanistic study. Immunohistochemistry (IHC) was used to further assess the relationship of MYSM1 with CRC diagnosis and prognosis. RESULTS: MYSM1 was significantly downregulated and was related to the overall survival (OS) of CRC patients. MYSM1 served as a CRC suppressor by inducing apoptosis and inhibiting cell proliferation, EMT, tumorigenic potential and metastasis. Mechanistically, MYSM1 directly bound to the promoter region of miR-200/CDH1, impaired the enrichment of repressive H2AK119ub1 modification and epigenetically enhanced miR-200/CDH1 expression. Testing of paired CRC patient samples confirmed the positive regulatory relationship between MYSM1 and miR-200/CDH1. Furthermore, silencing MYSM1 stimulated PI3K/AKT signaling and promoted EMT in CRC cells. More importantly, a positive association existed between MYSM1 expression and a favorable CRC prognosis. CONCLUSIONS: MYSM1 plays essential suppressive roles in CRC tumorigenesis and is a potential target for reducing CRC progression and distant metastasis.

[A novel compound heterozygous mutation in MYSM1 gene in a 1-month-old girl: a bone marrow failure syndrome 4 family survey and literature review].

Objective: To report the clinical manifestations and total exon detection results of one case of MYSM1 gene complex heterozygosity mutation of bone marrow failure syndrome 4 and the results of total exon detection of her family to provide a case phenotype for the early diagnosis of bone marrow failure syndrome 4. Methods: A 1-month-old girl with severe anemia was sequenced with trio-WES. Similarly, the family was also sequenced with tribe-WES to confirm the molecular diagnosis. BWA, GATK, and other software were used for annotation analysis of sequencing results. After polymerase chain reaction, Sanger sequencing was performed by ABI3730 sequencer to verify the target sequence. Moreover, the verification results were obtained by the sequence analysis software. The clinical diagnosis of this girl was reported and the relevant pieces of literature were reviewed. Results: The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts. However, CD3(-)CD19(+) B decreased. The child was identified with MYSM1 complex heterozygous mutation by whole-exome sequencing, NM_001085487.2:c.1607_c.1611delAAGAG and c.1432C>T, which was respectively inherited from his parents. Genealogy verification confirmed that the c.1432C>T mutation carried by the father was from the grandfather (father's father) , whereas the c.1607_c.1611delAAGAG mutation carried by the mother was from the grandfather (mother's father) , whereas the grandmothers, aunts, and uncle did not carry the mutation. The child was diagnosed with BMFS4 combined with clinical phenotypic and molecular genetic findings. Conclusion: This case provides a case phenotype for the early diagnosis of BMFS4 and extends the pathogenicity variation and phenotype spectrum of the MYSM1 gene. The newly discovered pathogenic variant of MYSM1 c. 1607_c.1611delAAGAG has not been reported at home or abroad.

Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1.

Myb-like SWIRM and MPN domains (MYSM1) is a chromatin-binding transcriptional regulator that mediates histone 2A deubiquitination, which plays a vital role in hematopoiesis and lymphocyte differentiation. Biallelic variants in MYSM1 cause a rare bone marrow failure syndrome (OMIM #618116). To date, only three pathogenic variants (E390*, R478*, and H656R) of MYSM1 have been reported in nine patients, and all variants are homozygous. Here, we describe a Chinese female patient who mainly presented with leukopenia, granulocytopenia, thrombocytopenia, severe anemia, and B-cell and natural killer cell deficiency in the peripheral blood, and was diagnosed with bone marrow failure. Trio whole-exome sequencing revealed a novel compound heterozygous variant in MYSM1 (c.399G > A, p.L133L, and c.1467C > G, p.Y489*). The c.399G > A synonymous variant is located at the 3'-end of exon 6, which is predicted to affect MYSM1 mRNA splicing. Analysis of the products obtained from the reverse transcription-polymerase chain reaction revealed that the c.399G > A variant leads to exon 6 skipping, resulting in a premature termination codon (c.321_399 del, p.V108Lfs*13). cDNA sequencing suggested that the c.1467C > G variant triggered nonsense-mediated mRNA degradation. Moreover, we identified a novel transcript of MYSM1 mRNA (missing exons 5 and 6) in human blood cells. Our results expand the mutation spectrum of MYSM1; additionally, this is the first report of a synonymous splicing variant that induces post-transcriptional skipping of exon 6 leading to a bone marrow failure syndrome phenotype.

MYSM1 Suppresses Cellular Senescence and the Aging Process to Prolong Lifespan.

Aging is a universal feature of life that is a major focus of scientific research and a risk factor in many diseases. A comprehensive understanding of the cellular and molecular mechanisms of aging are critical to the prevention of diseases associated with the aging process. Here, it is shown that MYSM1 is a key suppressor of aging and aging-related pathologies. MYSM1 functionally represses cellular senescence and the aging process in human and mice primary cells and in mice organs. MYSM1 mechanistically attenuates the aging process by promoting DNA repair processes. Remarkably, MYSM1 deficiency facilitates the aging process and reduces lifespan, whereas MYSM1 over-expression attenuates the aging process and increases lifespan in mice. The functional role of MYSM1 is demonstrated in suppressing the aging process and prolonging lifespan. MYSM1 is a key suppressor of aging and may act as a potential agent for the prevention of aging and aging-associated diseases.

MYSM1 Represses Innate Immunity and Autoimmunity through Suppressing the cGAS-STING Pathway.

The immune system is not only required for preventing threats exerted by pathogens but also essential for developing immune tolerance to avoid tissue damage. This study identifies a distinct mechanism by which MYSM1 suppresses innate immunity and autoimmunity. The expression of MYSM1 is induced upon DNA virus infection and by intracellular DNA stimulation. MYSM1 subsequently interacts with STING and cleaves STING K63-linked ubiquitination to suppress cGAS-STING signaling. Notably, Mysm1-deficient mice exhibit a hyper-inflammatory response, acute tissue damage, and high mortality upon virus infection. Moreover, in the PBMCs of patients with systemic lupus erythematosus (SLE), MYSM1 production decreases, while type I interferons and pro-inflammatory cytokine expressions increase. Importantly, MYSM1 treatment represses the production of IFNs and pro-inflammatory cytokines in the PBMCs of SLE patients. Thus, MYSM1 is a critical repressor of innate immunity and autoimmunity and is thus a potential therapeutic agent for infectious, inflammatory, and autoimmune diseases.

MYSM1-AR complex-mediated repression of Akt/c-Raf/GSK-3ß signaling impedes castration-resistant prostate cancer growth.

Epigenetic alterations that lead to dysregulated gene expression in the progression of castration-resistant prostate cancer (CRPC) remain elusive. Here, we investigated the role of histone deubiquitinase MYSM1 in the pathogenesis of prostate cancer (PCa). Tissues and public datasets of PCa were evaluated for MYSM1 levels. We explored the effects of MYSM1 on cell proliferation, senescence and viability both in vitro and in vivo. Integrative database analyses and co-immunoprecipitation assays were performed to elucidate genomic association of MYSM1 and MYSM1-involved biological interaction network in PCa. We observed that MYSM1 were downregulated in CRPC compared to localized prostate tumors. Knockdown of MYSM1 promoted cell proliferation and suppressed senescence of CRPC cells under condition of androgen ablation. MYSM1 downregulation enhanced the tumorigenic ability in nude mice. Integrative bioinformatic analyses of the significantly associated genes with MYSM1 revealed MYSM1-correlated pathways, providing substantial clues as to the role of MYSM1 in PCa. MYSM1 was able to bind to androgen receptor instead of increasing its expression and knockdown of MYSM1 resulted in activation of Akt/c-Raf/GSK-3ß signaling. Together, our findings indicate that MYSM1 is pivotal in CRPC pathogenesis and may be established as a potential target for future treatment.

Novel reno-protective mechanism of Aspirin involves H2AK119 monoubiquitination and Set7 in preventing type 1 diabetic nephropathy.

BACKGROUND: Even after several novel therapeutic approaches, the number of people with diabetic nephropathy (DN) still continues to increase globally, this suggest to find novel therapeutic strategies to prevent it completely. Recent reports, are indicating the ubiquitin proteasome system alterations in DN. Recently, we also showed that, histone H2AK119 mono-ubiquitination (H2AK119-Ub) found to regulate Set7, a key epigenetic enzyme in the development of renal fibrosis under type 1 diabetic condition. Hence, we aimed to study the role of a known 20s proteasome inhibitor Aspirin, on histone ubiquitination in the progression of DN. METHODS: Male Wistar rats were rendered diabetic using a single dose of Streptozotocin (55mgkg-1, ip). After 4 weeks, diabetic animals were grouped into respective groups and the drug, aspirin, low dose (25mgkg-1day-1), high dose (50mgkg-1day-1) was administered through po route. At the end of the study, kidneys from all the groups were collected and processed separately for glomerular isolation, protein isolation, and for histopathological studies. RESULTS: Aspirin administration, reduced the protein expression of Mysm1, increased the protein expression of H2AK119-Ub and thereby reduced the Set7 protein expression in glomeruli isolated from diabetic animals and prevented renal fibrosis. CONCLUSIONS: In conclusion, our results are clearly indicating that, aspirin prevents renal fibrosis in diabetic animals through decreasing the expression of Mysm1, increasing the expression of H2AK119-Ub and thereby decreasing the protein expression of Set7, which is a novel mechanism. Moreover, this mechanism may lay down a novel strategy to prevent DN completely in future.

MYSM1/miR-150/FLT3 inhibits B1a cell proliferation.

The aberrant expansion of B1a cells has been observed in several murine autoimmune disease models; however, the mechanism of such proliferation of B1a cells is still limited. Here, we identify that Myb Like, SWIRM And MPN Domains 1 (MYSM1), a histone H2A deubiquitinase, plays an intrinsic role in the proliferation of B1a cells where MYSM1 deficiency results in the increased proliferation of B1a cells in mice. We demonstrate that MYSM1 recruits c-Myc to the promoter of miR-150 and stimulates the transcription of miR-150. Our further investigation shows that miR-150 decreases FMS-like tyrosine kinase 3 (FLT3) in B1a cells. In agreement with our animal studies, the percentage of FLT3+ B1 cells in Systemic Lupus Erythematosus (SLE) patients is significantly higher than healthy control. Thus, this study uncovers a novel pathway MYSM1/miR-150/FLT3 that inhibits proliferation of B1a, which may be involved in the pathogenesis of SLE.