Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model

Chan, Perry M.

doi:10.1007/s13238-011-1020-7

Cited by 34 publications

(30 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been proposed that the altered juxtamemebrane domain (JM) domain of the FLT3/ITD mutant destabilizes the autoinhibited kinase conformation of FLT3, resulting in a high level of autophosphorylation of the receptor and its subsequent retention in the perinuclear region with prolonged exposure to perinuclear substrates such as STAT5. In contrast, the normal JM domain of FLT3/KD mutants is more efficiently processed and trafficked to the plasma membrane, and thus would activate downstream signals more similar to those of wild-type FLT3 (33). Consistent with this, we observed significantly higher levels of STAT5 phosphorylation, as well as increased expression of STAT5 downstream targets, in the BM of FLT3/ITD mice compared with FLT3/D835Y mice, supporting the idea that the two mutations have at least this one difference in the activation of downstream pathways.…”

Section: Discussionmentioning

confidence: 99%

“…These data suggest that, unlike the deficits in HSCs from FLT3/ITD mice, the HSC compartment in FLT3/D835Y mice appears less affected, with KSL SLAM populations and functional engraftment capacity closer to that of wild-type mice. (18,33). This lack of STAT5 activation has also been proposed to be one of the differences in signaling between FLT3/ITD and FLT3/KD mutants.…”

Section: Cd19mentioning

confidence: 99%

See 1 more Smart Citation

FLT3/D835Y mutation knock-in mice display less aggressive disease compared with FLT3/internal tandem duplication (ITD) mice

Bailey

Li²,

Duffield³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately one third of acute myeloid leukemia cases. The most common FLT3 mutations in acute myeloid leukemia are internal tandem duplication (ITD) mutations in the juxtamembrane domain (23%) and point mutations in the tyrosine kinase domain (10%). The mutation substituting the aspartic acid at position 838 (equivalent to the human aspartic acid residue at position 835) with a tyrosine (referred to as FLT3/D835Y hereafter) is the most frequent kinase domain mutation, converting aspartic acid to tyrosine. Although both of these mutations constitutively activate FLT3, patients with an ITD mutation have a significantly poorer prognosis. To elucidate the mechanisms behind this prognostic difference, we have generated a knock-in mouse model with a D838Y point mutation in FLT3 that corresponds to the FLT3/D835Y mutation described in humans. Compared with FLT3/ITD knock-in mice, the FLT3/D835Y knock-in mice survive significantly longer. The majority of these mice develop myeloproliferative neoplasms with a less-aggressive phenotype. In addition, FLT3/D835Y mice have distinct hematopoietic development patterns. Unlike the tremendous depletion of the hematopoietic stem cell compartment we have observed in FLT3/ITD mice, FLT3/D835Y mutant mice are not depleted in hematopoietic stem cells. Further comparisons of these FLT3/ D835Y knock-in mice with FLT3/ITD mice should provide an ideal platform for dissecting the molecular mechanisms that underlie the prognostic differences between the two different types of FLT3 mutations.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Cd19mentioning

confidence: 99%

FLT3/D835Y mutation knock-in mice display less aggressive disease compared with FLT3/internal tandem duplication (ITD) mice

Bailey

Li²,

Duffield³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Thus, prerequisite of the intracellular retention is the constitutive activity of the receptor mediating slowdown of its post‐translational biogenesis . In an “intracellular active kinase load” model Chan suggested that recruitment of phosphotyrosine‐binding domain‐containing proteins causes the retardation, but the molecular mechanism of FLT3 ITD retention in intracellular compartments is currently still not known.…”

Section: Introductionmentioning

confidence: 99%

Wild‐type FLT3 and FLT3 ITD exhibit similar ligand‐induced internalization characteristics

Kellner

Keil

Schindler

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

Class III receptor tyrosine kinases control the development of hematopoietic stem cells. Constitutive activation of FLT3 by internal tandem duplications (ITD) in the juxtamembrane domain has been causally linked to acute myeloid leukaemia. Oncogenic FLT3 ITD is partially retained in compartments of the biosynthetic route and aberrantly activates STAT5, thereby promoting cellular transformation. The pool of FLT3 ITD molecules in the plasma membrane efficiently activates RAS and AKT, which is likewise essential for cell transformation. Little is known about features and mechanisms of FLT3 ligand (FL)-dependent internalization of surface-bound FLT3 or FLT3 ITD. We have addressed this issue by internalization experiments using human RS4-11 and MV4-11 cells with endogenous wild-type FLT3 or FLT3 ITD expression, respectively, and surface biotinylation. Further, FLT3 wild-type, or FLT3 ITD-GFP hybrid proteins were stably expressed and characterized in 32D cells, and internalization and stability were assessed by flow cytometry, imaging flow cytometry, and immunoblotting. FL-stimulated surface-exposed FLT3 WT or FLT3 ITD protein showed similar endocytosis and degradation characteristics. Kinase inactivation by mutation or FLT3 inhibitor treatment strongly promoted FLT3 ITD surface localization, and attenuated but did not abrogate FL-induced internalization. Experiments with the dynamin inhibitor dynasore suggest that active FLT3 as well as FLT3 ITD is largely endocytosed via clathrin-dependent endocytosis. Internalization of kinase-inactivated molecules occurred through a different yet unidentified mechanism. Our data demonstrate that FLT3 WT and constitutively active FLT3 ITD receptor follow, despite very different biogenesis kinetics, similar internalization and degradation routes. K E Y W O R D S degradation, Fms-like tyrosine kinase 3 internal tandem duplications, GFP hybrid genes, oncogene, plasma membrane, receptor endocytosis, receptor tyrosine kinase | 4669 KELLNER Et aL.

show abstract

“…[1][2][3] FLT3 is expressed on hematopoietic stem and progenitor cells where it functions in cell differentiation, proliferation, and survival. After translation, FLT3 undergoes glycosylation in the endoplasmic reticulum to form an immature receptor and progresses to the Golgi complex where final glycosylation produces a mature receptor before it translocates to the surface.…”

Section: Introductionmentioning

confidence: 99%

Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia

Williams

Nguyen

et al. 2012

Blood

View full text Add to dashboard Cite

IntroductionFLT3 is a class III tyrosine kinase receptor that is composed of an extracellular domain that binds FLT3 ligand (FL), a single-pass transmembrane domain, a short juxtamembrane domain, and an interrupted kinase domain that contains a typical activation loop. [1][2][3] FLT3 is expressed on hematopoietic stem and progenitor cells where it functions in cell differentiation, proliferation, and survival. After translation, FLT3 undergoes glycosylation in the endoplasmic reticulum to form an immature receptor and progresses to the Golgi complex where final glycosylation produces a mature receptor before it translocates to the surface. Once at the surface, FLT3 binding to FL leads to receptor dimerization, autophosphorylation, and activation. 4 The transient activation of FLT3 by FL activates several downstream pathways, including Ras/MAPK, PI3K/AKT, and JAK/STAT. [4][5][6][7][8][9] Besides FL binding, FLT3 can also be constitutively activated by mutation, either internal tandem duplications (ITD) of the juxtamembrane domain or point mutations of the tyrosine kinase domain (TKD), that produce altered signaling. [10][11][12] The ITD mutations result in in-frame repeats of varying length. Most TKD mutations result in missense mutations of the activation loop, most frequently the D835 residue. The activating mutations of FLT3 are found in approximately 30% of patients with acute myeloid leukemia (AML). 13,14 When cytokine-dependent cell lines are engineered to express FLT3 mutations they are transformed to factor independence in vitro. FLT3/ITD knock-in mice and mice whose bone marrow is retrovirally transduced with mutant FLT3 develop a lethal myeloproliferative disease. [15][16][17][18] When combined with other mutations such as MLL-AF9, AML1/ETO, NUP-98/HOXD13, or NPM known to occur in human AML, FLT3/ITD mutations cooperate to cause acute leukemia in the mice. [19][20][21][22] This evidence indicates a cooperative role for FLT3 in leukemia and has led to the development of drugs that target FLT3 kinase activity. Numerous tyrosine kinase inhibitors (TKIs) have been identified that all inhibit FLT3/ITD phosphorylation and are cytotoxic to FLT3/ITD-dependent cells. [23][24][25] Wild-type FLT3 is often inhibited to a lesser extent by many of the FLT3 TKI. Some FLT3 TKI have very little activity against certain FLT3 kinase domain-activating mutations, particularly D835Y, rendering the cells functionally resistant. [26][27][28] In addition, there are several mutations within or outside the drug-binding cleft that have been selected for in vitro or in vivo that impart varying levels of resistance to TKI. 28-32 Thus, newer TKIs or a different class of drugs that can inhibit FLT3 are merited for management of leukemias that express FLT3 as a significant transformative component of malignancy.Statins have been developed to lower cholesterol and total triglyceride levels in patients who are considered to be at risk for heart attack based in part on serum cholesterol levels and are considered to be very safe drugs. 33 ...

show abstract

Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model

Cited by 34 publications

References 43 publications

FLT3/D835Y mutation knock-in mice display less aggressive disease compared with FLT3/internal tandem duplication (ITD) mice

FLT3/D835Y mutation knock-in mice display less aggressive disease compared with FLT3/internal tandem duplication (ITD) mice

Wild‐type FLT3 and FLT3 ITD exhibit similar ligand‐induced internalization characteristics

Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia

Contact Info

Product

Resources

About