FLT3/ITD expression increases expansion, survival and entry into cell cycle of human haematopoietic stem/progenitor cells

Li, Li; Piloto, Obdulio; Kim, Kyu-Tae; Ye, Zhaohui; Nguyen, Ho Bao; Yu, Xiaobing; Levis, Mark J.; Cheng, Linzhao; Small, Donald

doi:10.1111/j.1365-2141.2007.06525.x

Cited by 36 publications

(29 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4I and J). Previous studies have shown that FLT3/ITD promotes cell growth and survival (40). Taken together, our results suggest that the activation of multiple signaling pathways is required for NIDF cells to induce AML (Fig.…”

Section: Discussionsupporting

confidence: 81%

IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia

Ogawara¹,

Katsumoto²,

Aikawa³

et al. 2015

Cancer Research

View full text Add to dashboard Cite

IDH1 and IDH2 mutations occur frequently in acute myeloid leukemia (AML) and other cancers. The mutant isocitrate dehydrogenase (IDH) enzymes convert a-ketoglutarate (a-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of a-KG-dependent dioxygenases. To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of AML in which mice were transplanted with nucleophosmin1 (NPM) þ/À hematopoietic stem/progenitor cells cotransduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H, and FLT3/ITD), which often occur simultaneously in human AML patients. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q was necessary for the engraftment or survival of NPMc þ cells in vivo. Gene expression analysis indicated that NPMc increased expression of Hoxa9. IDH2/R140Q also increased the level of Meis1 and activated the hypoxia pathway in AML cells. IDH2/R140Q decreased the 5hmC modification and expression of some differentiation-inducing genes (Ebf1 and Spib). Taken together, our results indicated that IDH2 mutation is critical for the development and maintenance of AML stem-like cells, and they provided a preclinical justification for targeting mutant IDH enzymes as a strategy for anticancer therapy.

show abstract

Section: Discussionsupporting

confidence: 81%

IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia

Ogawara¹,

Katsumoto²,

Aikawa³

et al. 2015

Cancer Research

View full text Add to dashboard Cite

show abstract

“…The concept of LSC also supports the hypothesis that class I mutations are secondary to class II mutations. 213,214 In agreement with this hypothesis is that some patients with FLT3 mutation at diagnosis relapse without mutation. 26,44 Another event implicated in leukemogenesis is the deregulation, in blast cells, of genes involved in the maintenance of the stem cell phenotype.…”

Section: Gene Mutations In Acute Myeloid Leukemiasupporting

confidence: 55%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

show abstract

“…46 Activating mutation of FLT3 have also been shown to increase expression of MYC in AMLs. 47 Hemizygous loss of APC detected in this work is known to cause aberrant activation of the WNT pathway in leukemia, 48,49 which may also lead to overexpression of MYC. EXT1 gene was found to be essential for the coordinated activation of WNT signaling during Drosophila development.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome

Nikolaev

Santoni

Vannier

et al. 2013

Blood

View full text Add to dashboard Cite

Key Points• DS TMD shows no DNA rearrangements and a low rate of mutations other than GATA1.• DS AMKL always has rearrangements and mutations in genes known for leukemic progression; affected pathways share upregulation of MYC.Some neonates with Down syndrome (DS) are diagnosed with self-regressing transient myeloproliferative disorder (TMD), and 20% to 30% of those progress to acute megakaryoblastic leukemia (AMKL). We performed exome sequencing in 7 TMD/AMKL cases and copy-number analysis in these and 10 additional cases. All TMD/AMKL samples contained GATA1 mutations. No exome-sequenced TMD/AMKL sample had other recurrently mutated genes. However, 2 of 5 TMD cases, and all AMKL cases, showed mutations/deletions other than GATA1, in genes proven as transformation drivers in non-DS leukemia (EZH2, APC, FLT3, JAK1, PARK2-PACRG, EXT1, DLEC1, and SMC3). One patient at the TMD stage revealed 2 clonal expansions with different GATA1 mutations, of which 1 clone had an additional driver mutation. Interestingly, it was the other clone that gave rise to AMKL after accumulating mutations in 7 other genes. Data suggest that GATA1 mutations alone are sufficient for clonal expansions, and additional driver mutations at the TMD stage do not necessarily predict AMKL progression. Later in infancy, leukemic progression requires "third-hit driver" mutations/somatic copy-number alterations found in non-DS leukemias. Putative driver mutations affecting WNT (winglessrelated integration site), JAK-STAT (Janus kinase/signal transducer and activator of transcription), or MAPK/PI3K (mitogenactivated kinase/phosphatidylinositol-3 kinase) pathways were found in all cases, aberrant activation of which converges on overexpression of MYC. (Blood. 2013;122(4):554-561)

show abstract

FLT3/ITD expression increases expansion, survival and entry into cell cycle of human haematopoietic stem/progenitor cells

Cited by 36 publications

References 47 publications

IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia

IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome

Contact Info

Product

Resources

About