Direct role of <scp>FLT</scp>3 in regulation of early lymphoid progenitors

Zriwil, Alya; Böiers, Charlotta; Kristiansen, Trine A.; Wittmann, Lilian; Yuan, Joan; Nerlov, Claus; Sitnicka, Ewa; Jacobsen, Sten Eirik W.

doi:10.1111/bjh.15578

Cited by 15 publications

(15 citation statements)

References 52 publications

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“…Flt3 fl/fl Vav1-Cre were generated to investigate the role of Flt3 in lymphoid development, prior to lymphoid specification [16]. Consistent with the findings detailed above, the panhematopoietic loss of Flt3 had no effect on HSC.…”

Section: Flt3 Signaling In B Lymphopoiesismentioning

confidence: 59%

“…An additional role for Flt3 in peripheral B cell homeostasis was suggested in results obtained from mixed radiation chimeras transplanted with fetal liver cells from Flt3 fl/fl Rag1-Cre and wildtype competitor cells. Eight weeks post-transplant the authors found impaired reconstitution of B1a, marginal zone B, and conventional B cells in the peritoneal cavity and spleen of the transplant recipients [16]. Thus, in addition to being a critical regulator of BM B lymphopoiesis, Flt3 signaling plays roles in peripheral B cell maturation and class switch recombination.…”

Section: Regulation Of Peripheral B Development By Flt3/flmentioning

confidence: 97%

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Flt3 Signaling in B Lymphocyte Development and Humoral Immunity

Medina

2022

IJMS

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The Class III receptor tyrosine kinase Flt3 and its ligand, the Flt3-ligand (FL), play an integral role in regulating the proliferation, differentiation, and survival of multipotent hematopoietic and lymphoid progenitors from which B cell precursors derive in bone marrow (BM). More recently, essential roles for Flt3 signaling in the regulation of peripheral B cell development and affinity maturation have come to light. Experimental findings derived from a multitude of mouse models have reinforced the importance of molecular and cellular regulation of Flt3 and FL in lymphohematopoiesis and adaptive immunity. Here, we provide a comprehensive review of the current state of the knowledge regarding molecular and cellular regulation of Flt3/FL and the roles of Flt3 signaling in hematopoietic stem cell (HSC) activation, lymphoid development, BM B lymphopoiesis, and peripheral B cell development. Cumulatively, the literature has reinforced the importance of Flt3 signaling in B cell development and function. However, it has also identified gaps in the knowledge regarding Flt3-dependent developmental-stage specific gene regulatory circuits essential for steady-state B lymphopoiesis that will be the focus of future studies.

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Section: Flt3 Signaling In B Lymphopoiesismentioning

confidence: 59%

Section: Regulation Of Peripheral B Development By Flt3/flmentioning

confidence: 97%

Flt3 Signaling in B Lymphocyte Development and Humoral Immunity

Medina

2022

IJMS

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“…Expression pattern and conditional knockout mouse studies showed that FLT3 expression is maintained and critical at the pro-B stage, where RAG expression is induced. 39 Therefore, our data highlight how neighbor genes can be involved in a deleterious loop linking gene expression, chromatin structure, and oncogenic activation, suggesting a mechanistic framework for deregulation of ectopic genes by RAG-mediated alterations.…”

Section: Discussionmentioning

confidence: 79%

Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL

Passet

Kim

Gachet

et al. 2022

Blood

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Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA-seq and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of two genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-seq and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n=26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph-negative B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n=17/723, 2.4%) were frequently young women (M/F ratio 0.2, P=0.002, median age 31 years). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% versus 3%, P=0.017) and higher post-induction MRD levels (MRD ≥ 10-4, 93%, versus 46%, P<0.001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% versus 32.4%, P=0.004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults. Study can be found on https://clinicaltrials.gov NCT00327678 and NCT02617004.

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“…The Flt-3L is an important regulator of lymphopoiesis. Its receptor is expressed on multipotent progenitors and sustained on the earliest B-cell and T-cell progenitors [ 24 , 25 ]. Flt-3L is found as membrane-bound and soluble forms.…”

Section: Discussionmentioning

confidence: 99%

Lymphomagenesis predictors and related pathogenesis

Ruiz-Ordóñez

Piedrahita

Arévalo

et al. 2021

Journal of Translational Autoimmunity

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Sjögren’s syndrome (SS) is a systemic autoimmune disease characterised by a wide range of clinical manifestations and complications, including B-cell lymphoma. This study aims to describe the predictors associated with lymphomagenesis in patients with Sjögren’s syndrome, emphasising the pathophysiological bases that support this association. We performed a review of the literature published through a comprehensive search strategy in PubMed/MEDLINE, Scopus, and Web of science. Forty publications describing a total of 45,208 patients with SS were retrieved. The predictors were grouped according to their pathophysiological role in the lymphoproliferation process. Also, some new biomarkers such as MicroRNAs, P2X7 receptor-NLRP3 inflammasome, Thymic stromal lymphopoietin, and Three-prime repair exonuclease 1 (TREX1) were identified. The knowledge of the pathophysiology allows the discrimination of markers that participate in the initial stages. Considering that the lymphoproliferation process includes the progression of lymphoma towards more aggressive subtypes, it is essential to recognise biomarkers associated with a worse prognosis.

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Direct role of FLT3 in regulation of early lymphoid progenitors

Cited by 15 publications

References 52 publications

Flt3 Signaling in B Lymphocyte Development and Humoral Immunity

Flt3 Signaling in B Lymphocyte Development and Humoral Immunity

Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL

Lymphomagenesis predictors and related pathogenesis

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