Kras Is Critical for B Cell Lymphopoiesis

Chen, Yuhong; Zheng, Yongwei; You, Xiaona; Yu, Mei; Fu, Guoping; X, Su; Zhou, Fen; Zhu, Wen; Wu, Zhihong; Zhang, Jing; Wen, Renren; Wang, Demin

doi:10.4049/jimmunol.1502112

Cited by 23 publications

(28 citation statements)

References 34 publications

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“…S7). Consistent with our finding, recent work from Chen and colleagues showed that the ERK1/2 pathway is downregulated in Kras 2/2 B cells, which is associated with B cell differentiation defects at both pre-B cell and mature B cell stages [41]. Together, these data indicate loss of Kras leads to various defects in differentiated hematopoietic cells, which could contribute to reduced reconstitution of Kras 2/2 -derived cells in recipients.…”

Section: Discussionsupporting

confidence: 92%

Kras is Required for Adult Hematopoiesis

et al. 2016

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Previous studies indicate that Kras is dispensable for fetal liver hematopoiesis, but its rolein adult hematopoiesis remains unclear. Here, we generated a Kras conditional knockout allele to address this question. Deletion of Kras in adult bone marrow is mediated by Vav-Cre or inducible Mx1-Cre. We find that loss of Kras leads to greatly reduced TPO signaling in hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), while SCF-evoked ERK1/2 activation is not affected. The compromised TPO signaling is associated with reduced long term- and intermediate-term HSC compartments and a bias towards myeloid differentiation in MPPs. Although GM-CSF-evoked ERK1/2 activation is only moderately decreased in Kras−/− myeloid progenitors, it is blunted in neutrophils and neutrophil survival is significantly reduced in vitro. At 9–12 months old, Kras conditional knockout mice develop profound hematopoietic defects, including splenomegaly, an expanded neutrophil compartment, and reduced B cell number. In a serial transplantation assay, the reconstitution potential of Kras−/− bone marrow cells is greatly compromised, which is attributable to defects in the self-renewal of Kras−/− HSCs and defects in differentiated hematopietic cells. Our results demonstrate that Kras is a major regulator of TPO and GM-CSF signaling in specific populations of hematopoietic cells and its function is required for adult hematopoiesis.

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Section: Discussionsupporting

confidence: 92%

Kras is Required for Adult Hematopoiesis

et al. 2016

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“…This could contribute to the enhanced constitutive activation of the p-Akt/p-S6 pathway in IgH.TE μ CLL as reported previously ( 23 , 24 ). Additionally, genes involved in KRAS signaling were highly expressed in both CLL subsets, consistent with its essential role in B cell lymphopoesis ( 60 ), particularly for B-1 cells recognizing PtC ( 61 ).…”

Section: Discussionmentioning

confidence: 66%

Identification of Distinct Unmutated Chronic Lymphocytic Leukemia Subsets in Mice Based on Their T Cell Dependency

et al. 2018

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Chronic lymphocytic leukemia (CLL) can be divided into prognostically distinct subsets with stereotyped or non-stereotyped, mutated or unmutated B cell receptors (BCRs). Individual subsets vary in antigen specificity and origin, but the impact of antigenic pressure on the CLL BCR repertoire remains unknown. Here, we employed IgH.TEμ mice that spontaneously develop CLL, expressing mostly unmutated BCRs of which ~35% harbor VH11-2/Vκ14-126 and recognize phosphatidylcholine. Proportions of VH11/Vκ14-expressing CLL were increased in the absence of functional germinal centers in IgH.TEμ mice deficient for CD40L or activation-induced cytidine deaminase. Conversely, in vivo T cell-dependent immunization decreased the proportions of VH11/Vκ14-expressing CLL. Furthermore, CLL onset was accelerated by enhanced BCR signaling in Siglec-G−/− mice or in mice expressing constitutively active Bruton's tyrosine kinase. Transcriptional profiling revealed that VH11 and non-VH11 CLL differed in the upregulation of specific pathways implicated in cell signaling and metabolism. Interestingly, principal component analyses using the 148 differentially expressed genes revealed that VH11 and non-VH11 CLL clustered with BCR-stimulated and anti-CD40-stimulated B cells, respectively. We identified an expression signature consisting of 13 genes that were differentially expressed in a larger panel of T cell-dependent non-VH11 CLL compared with T cell-independent VH11/Vκ14 or mutated IgH.TEμ CLL. Parallel differences in the expression of these 13 signature genes were observed between heterogeneous and stereotypic human unmutated CLL. Our findings provide evidence for two distinct unmutated CLL subsets with a specific transcriptional signature: one is T cell-independent and B-1 cell-derived while the other arises upon antigen stimulation in the context of T-cell help.

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“…Similarly, the ERK1/2 pathway is down-regulated in Kras ¡/¡ B cells, which is associated with B cell differentiation defects at both pre-B cell and mature B cell stages. 10 These results reveal a surprising, indispensible role of Kras in mediating cell typeand cykokine-specific ERK1/2 activation, especially in differentiated cells (e.g. neutrophils).…”

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confidence: 87%

The mystery of oncogenicKRAS: Lessons from studying its wild-type counter part

et al. 2016

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Using conditional knock-in mouse models, we and others have shown that despite the very high sequence identity between Nras and Kras proteins, oncogenic Kras displays a much stronger leukemogenic activity than oncogenic Nras in vivo. In this manuscript, we will summarize our recent work of characterizing wild-type Kras function in adult hematopoiesis and in oncogenic Kras-induced leukemogenesis. We attribute the strong leukemogenic activity of oncogenic Kras to 2 unique aspects of Kras signaling. First, Kras is required in mediating cell type-and cytokine-specific ERK1/2 signaling. Second, oncogenic Kras, but not oncogenic Nras, induces hyperactivation of wild-type Ras, which significantly enhances Ras signaling in vivo. We will also discuss a possible mechanism that mediates oncogenic Krasevoked hyperactivation of wild-type Ras and a potential approach to down-regulate oncogenic Kras signaling. In mammals, there are 3 Ras genes (Hras, Nras, and Kras) encoding 4 homologous 21kD proteins: Hras, Nras, Kras4A and Kras4B. 1 The first 85 amino-terminal residues are identical and the middle 78 amino acids share an 85% -90% identity among all Ras isoforms, while the last 25 amino acids at the carboxyl-terminus are highly variable. 2 In haematopoietic neoplasms, oncogenic mutations in the NRAS and KRAS genes are common, but rare in the HRAS gene. 2 Despite the high similarity in protein sequences and largely overlapping expression patterns, accumulating evidence suggest that Kras G12D/C expressed from its endogenous locus demonstrates much stronger leukemogenic activity than oncogenic Nras alleles (including Nras G12D alleles) (Fig. 1). Using conditional knock-in mouse models, we and others characterized multiple oncogenic Ras alleles in a pure C57BL/6 background, including the weak Nras G12D/ C , the intermediate Nras Q61R/C and Nras G12D/G12D , and the strong Kras G12D/C . 3-8 All of these models involve a conditional knock-in oncogenic Ras allele and the interferon-inducible Mx1-Cre. Upon polyinosinic-polycytidylic acid (pI-pC) injections to induce the expression of Cre and subsequently the oncogenes, Kras G12D/C mice die rapidly, while Nras G12D/G12D and Nras G12D/C mice show incrementally prolonged survival (Fig. 1A). To eliminate the impact of acute interferon signaling on animal survival, we also took advantage of the leaky expression of Mx1-Cre over the time. Again, the non-pIpC treated Kras G12D/C mice display a significantly shorter survival than the corresponding Nras G12D/G12D mice (Fig. 1B). These results clearly demonstrate that oncogenic Kras is a much more potent oncogene than oncogenic Nras in leukemogenesis.To decipher the unique function of oncogenic Kras signaling in leukemogenesis, we first investigated how loss of wild-type (WT) Kras impacts on adult hematopoiesis. 9 We found that loss of Kras leads to greatly reduced TPO signaling in haematopoietic stem cells (HSCs), while SCF-evoked ERK1/2 activation is not affected. The compromised TPO signaling is associated with reduced long term-and i...

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Kras Is Critical for B Cell Lymphopoiesis

Cited by 23 publications

References 34 publications

Kras is Required for Adult Hematopoiesis

Kras is Required for Adult Hematopoiesis

Identification of Distinct Unmutated Chronic Lymphocytic Leukemia Subsets in Mice Based on Their T Cell Dependency

The mystery of oncogenicKRAS: Lessons from studying its wild-type counter part

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