Arid2 regulates hematopoietic stem cell differentiation in normal hematopoiesis

Bluemn, Theresa; Schmitz, Jesse; Chen, Yuhong; Zheng, Yongwei; Zhang, Yongguang; Zheng, Shikan; Burns, Robert T.; DeJong, Joshua; Christiansen, Luke; Izaguirre-Carbonell, Jesus; Wang, Demin; Zhu, Nan

doi:10.1016/j.exphem.2020.12.004

Cited by 13 publications

(6 citation statements)

References 44 publications

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“…First, in B-ALL case #03 with complex karyotype and BCR::ABL1 fusion, OGM detected infrachromosomal deletions characteristic of B-ALL, namely recurrent deletions in IKZF1 , PAX5 , BTG1 , ADD3 genes, and CDKN2A biallelic deletion ( Figure 4 ) [ 21 ]. OGM also showed a 135 kb-deletion encompassing the 5′-part of KRAS and a translocation t(12;13) inducing a putative novel fusion of the WDFY2 gene with the ARID2 gene, a component of the SWI/SNF complex with tumor suppressive properties that play a role in the differentiation of hematopoietic stem cells [ 22 , 23 ]. Interestingly this translocation is associated with an intragenic deletion of ARID2 , which could result in haploinsufficiency.…”

Section: Resultsmentioning

confidence: 99%

Optical Genome Mapping in Routine Cytogenetic Diagnosis of Acute Leukemia

Soler

Ouédraogo

Goumy

et al. 2023

Cancers

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Cytogenetic aberrations are found in 65% of adults and 75% of children with acute leukemia. Specific aberrations are used as markers for the prognostic stratification of patients. The current standard cytogenetic procedure for acute leukemias is karyotyping in combination with FISH and RT-PCR. Optical genome mapping (OGM) is a new technology providing a precise identification of chromosomal abnormalities in a single approach. In our prospective study, the results obtained using OGM and standard techniques were compared in 29 cases of acute myeloid (AML) or lymphoblastic leukemia (ALL). OGM detected 73% (53/73) of abnormalities identified by standard methods. In AML cases, two single clones and three subclones were missed by OGM, but the assignment of patients to cytogenetic risk groups was concordant in all patients. OGM identified additional abnormalities in six cases, including one cryptic structural variant of clinical interest and two subclones. In B-ALL cases, OGM correctly detected all relevant aberrations and revealed additional potentially targetable alterations. In T-ALL cases, OGM characterized a complex karyotype in one case and identified additional abnormalities in two others. In conclusion, OGM is an attractive alternative to current multiple cytogenetic testing in acute leukemia that simplifies the procedure and reduces costs.

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Section: Resultsmentioning

confidence: 99%

Optical Genome Mapping in Routine Cytogenetic Diagnosis of Acute Leukemia

Soler

Ouédraogo

Goumy

et al. 2023

Cancers

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“…4C and S4A ). Many of these proteins (Arid2, Csf1r, Prtn3, Anxa1, Anxa3, and S100a9) are associated with terminal differentiation [ 35 , 36 ], and the decrease in their expression is thus in line with the rapid differentiation block induced by MLL::ENL (Fig. 3A, B ).…”

Section: Resultsmentioning

confidence: 96%

A complex interplay of intra- and extracellular factors regulates the outcome of fetal- and adult-derived MLL-rearranged leukemia

Jassinskaja,

Ghosh,

Watral

et al. 2024

Leukemia

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Infant and adult MLL1/KMT2A-rearranged (MLLr) leukemia represents a disease with a dismal prognosis. Here, we present a functional and proteomic characterization of in utero-initiated and adult-onset MLLr leukemia. We reveal that fetal MLL::ENL-expressing lymphomyeloid multipotent progenitors (LMPPs) are intrinsically programmed towards a lymphoid fate but give rise to myeloid leukemia in vivo, highlighting a complex interplay of intra- and extracellular factors in determining disease subtype. We characterize early proteomic events of MLL::ENL-mediated transformation in fetal and adult blood progenitors and reveal that whereas adult pre-leukemic cells are mainly characterized by retained myeloid features and downregulation of ribosomal and metabolic proteins, expression of MLL::ENL in fetal LMPPs leads to enrichment of translation-associated and histone deacetylases signaling proteins, and decreased expression of inflammation and myeloid differentiation proteins. Integrating the proteome of pre-leukemic cells with their secretome and the proteomic composition of the extracellular environment of normal progenitors highlights differential regulation of Igf2 bioavailability, as well as of VLA-4 dimer and its ligandome, upon initiation of fetal- and adult-origin leukemia, with implications for human MLLr leukemia cells’ ability to communicate with their environment through granule proteins. Our study has uncovered opportunities for targeting ontogeny-specific proteomic vulnerabilities in in utero-initiated and adult-onset MLLr leukemia.

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“…Hence, an adequate SWI/SNF function is critical for several differentiation processes, including hematopoiesis and hematopoietic stem cell (HSC) maintenance [ 32 – 34 ]. However, SWI/SNF complexes may play opposing roles in normal and in malignant hematopoiesis, adding a layer of complexity to their function [ 35 – 37 ].…”

Section: Swi/snf Complexes and Their Role In Hematopoiesismentioning

confidence: 99%

SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities

et al. 2023

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Hematological malignancies are a highly heterogeneous group of diseases with varied molecular and phenotypical characteristics. SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes play significant roles in the regulation of gene expression, being essential for processes such as cell maintenance and differentiation in hematopoietic stem cells. Furthermore, alterations in SWI/SNF complex subunits, especially in ARID1A/1B/2, SMARCA2/4, and BCL7A, are highly recurrent across a wide variety of lymphoid and myeloid malignancies. Most genetic alterations cause a loss of function of the subunit, suggesting a tumor suppressor role. However, SWI/SNF subunits can also be required for tumor maintenance or even play an oncogenic role in certain disease contexts. The recurrent alterations of SWI/SNF subunits highlight not only the biological relevance of SWI/SNF complexes in hematological malignancies but also their clinical potential. In particular, increasing evidence has shown that mutations in SWI/SNF complex subunits confer resistance to several antineoplastic agents routinely used for the treatment of hematological malignancies. Furthermore, mutations in SWI/SNF subunits often create synthetic lethality relationships with other SWI/SNF or non-SWI/SNF proteins that could be exploited therapeutically. In conclusion, SWI/SNF complexes are recurrently altered in hematological malignancies and some SWI/SNF subunits may be essential for tumor maintenance. These alterations, as well as their synthetic lethal relationships with SWI/SNF and non-SWI/SNF proteins, may be pharmacologically exploited for the treatment of diverse hematological cancers.

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Arid2 regulates hematopoietic stem cell differentiation in normal hematopoiesis

Cited by 13 publications

References 44 publications

Optical Genome Mapping in Routine Cytogenetic Diagnosis of Acute Leukemia

Optical Genome Mapping in Routine Cytogenetic Diagnosis of Acute Leukemia

A complex interplay of intra- and extracellular factors regulates the outcome of fetal- and adult-derived MLL-rearranged leukemia

SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities

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