<i>Kras</i> is Required for Adult Hematopoiesis

Damnernsawad, Alisa; Kong, Guangyao; Wen, Zhi Hong; Liu, Yangang; Rajagopalan, Adhithi; You, Xiaona; Wang, Jinyong; Zhou, Yun; Ranheim, Erik A.; Luo, Hongbo; Chang, Qiang; Zhang, Jing

doi:10.1002/stem.2355

Cited by 32 publications

(34 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We then generated compound Kras LSL G12D/1 ;Sos1 fl/fl ;Vav-Cre mice 10 (referred to as Kras;Sos1 2/2 mice thereafter) with Vav-Cre-mediated Kras G12D expression and Sos1 deletion. Unlike the Vav-iCre that drives oncogenic Kras expression in both fetal liver hematopoietic and endothelial cells, and thus leads to an embryonic lethality, 11 the Vav-Cre we used in our study 12,13 drove oncogenic Kras expression more strictly in the hematopoietic system after embryonic day 11.5, and thus approximately two-thirds of Kras LSL G12D/1 ;Vav-Cre (Kras) mice survived until adulthood (supplemental Table 1). As a consequence, approximately two-thirds of Kras;Sos1 2/2 mice also reached adulthood (supplemental Table 2).…”

Section: Sos1 Deletion Abolishes Oncogenic Kras-induced Hyperactivatimentioning

confidence: 99%

Unique dependence on Sos1 in KrasG12D-induced leukemogenesis

You

Kong

Ranheim

et al. 2018

Blood

Self Cite

View full text Add to dashboard Cite

Abstract We and others have previously shown that KrasG12D is a much more potent oncogene than oncogenic Nras in hematological malignancies. We attributed the strong leukemogenic activity of KrasG12D at least partially to its unique capability to hyperactivate wild-type (WT) Nras and Hras. Here, we report that Sos1, a guanine nucleotide exchange factor, is required to mediate this process. Sos1 is overexpressed in KrasG12D/+ cells, but not in NrasQ61R/+ and NrasG12D/+ cells. KrasG12D proteins form a complex with Sos1 in vivo. Sos1 deficiency attenuates hyperactivation of WT Nras, Hras, and the downstream ERK signaling in KrasG12D/+ cells. Thus, Sos1 deletion ameliorates oncogenic Kras-induced myeloproliferative neoplasm (MPN) phenotypes and prolongs the survival of KrasG12D/+ mice. In contrast, Sos1 is dispensable for hyperactivated granulocyte-macrophage colony-stimulating factor signaling in NrasQ61R/+ cells, and Sos1−/− does not affect MPN phenotypes in NrasQ61R/+ mice. Moreover, the survival of KrasG12D/+; Sos1−/− recipients is comparable to that of KrasG12D/+ recipients treated with combined MEK and JAK inhibitors. Our study suggests that targeting Sos1-oncogenic Kras interaction may improve the survival of cancer patients with KRAS mutations.

show abstract

Section: Sos1 Deletion Abolishes Oncogenic Kras-induced Hyperactivatimentioning

confidence: 99%

Unique dependence on Sos1 in KrasG12D-induced leukemogenesis

You

Kong

Ranheim

et al. 2018

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…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 intermediate-term HSC compartments and their reduced selfrenewal capability (Fig.…”

mentioning

confidence: 90%

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…All mouse lines were maintained in a pure C57BL/6 genetic background (>N10). Mice bearing a conditional oncogenic Nras allele (Nras Lox-stop-Lox (LSL) G12D/+ ) were crossed to Vav-Cre (Damnernsawad et al, 2016) mice to generate the experimental mice, including Nras LSL G12D/+ ; Vav-Cre, and Vav-Cre mice. These mice were genotyped as previously described Wang et al, 2011).…”

Section: Genetically Engineered Mouse Modelsmentioning

confidence: 99%

RASmutations drive proliferative chronic myelomonocytic leukemia via activation of a novel KMT2A-PLK1 axis

Vorobyev

Lasho

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

word count:ABSTRACT Chronic myelomonocytic leukemia (CMML) is an aggressive hematological malignancy with limited treatment options. Whole exome (WES) and targeted sequencing of several independent cohorts of CMML patients, comparing dysplastic (dCMML) to proliferative (pCMML) CMML, as well as paired chronic phase disease and acute leukemic transformation (LT), associate acquisition of oncogenic RAS pathway mutations, the most common being NRAS G12D , with aggressive disease and with disease progression. Using patient derived progenitor colony assays and a NRAS G12D -Vav-Cre mouse model, we further demonstrate the role of mutant RAS signaling in driving and maintaining pCMML phenotype. RNA-sequencing links RAS pathway mutations with an increased expression of genes encoding the mitotic checkpoint kinases PLK1 and WEE1. Further, we dmeoinstrated that non-mutated lysine methyltransferase KMT2A (MLL1) acts as mediator of NRAS-induced PLK1 and WEE1 expression. Finally, we demonstrate the translational value of our findings by showing that pharmacological PLK1 inhibition decreases monocytosis and hepatosplenomegaly while improving hematopoiesis in RAS mutant patient-derived xenografts. Hence, we define severe CMML as oncogenic RAS pathway-enriched malignancies, with a unique gene expression profile regulated by KMT2A, amenable to therapeutic intervention. RESULTS RAS pathway mutations correlate with WHO-defined proliferative CMML (pCMML)Analysis was first focused on chronic phase CMML, especially with regards to the phenotypic and survival differences between WHO-defined dCMML and pCMML subtypes. Univariate P.

show abstract

Kras is Required for Adult Hematopoiesis

Cited by 32 publications

References 42 publications

Unique dependence on Sos1 in KrasG12D-induced leukemogenesis

Unique dependence on Sos1 in KrasG12D-induced leukemogenesis

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

RASmutations drive proliferative chronic myelomonocytic leukemia via activation of a novel KMT2A-PLK1 axis

Contact Info

Product

Resources

About