Hox genes in hematopoiesis and leukemogenesis

Argiropoulos, Bob; Humphries, R. Keith

doi:10.1038/sj.onc.1210760

Cited by 432 publications

(393 citation statements)

References 139 publications

Supporting

Mentioning

375

Contrasting

Unclassified

Order By: Relevance

“…Among the genetic markers that has been previously studied in CN-AML patients are Fms-related tyrosine kinase 3 gene (FLT3) mutations [2][3][4][5], the nucleophosmin gene (NPM1) mutations [6][7][8][9][10][11][12][13][14][15], ERG [16,17] and BAALC [18][19][20][21][22] expression levels. Although studies concerning the prognostic relevance of BAALC [18] and ERG expression [16,17] in adult AML patients with CN AML become fully clear; the studies regarding their expression and prognostic impact in pediatric AML are few and of controversial results.…”

Section: Introductionmentioning

confidence: 99%

The Prognostic Relevance of BAALC and ERG Expression Levels in Cytogenetically Normal Pediatric Acute Myeloid Leukemia

Aref

Khodary

Zeed

et al. 2014

Indian J Hematol Blood Transfus

View full text Add to dashboard Cite

Cytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). About 45 % of de novo adult AML and 20 % of pediatric AML lack cytogenetic abnormalities, so identification of predictive molecular markers might improve therapy. Mutation status of FLT3, NPM1 genes and gene expression levels of ERG, BAALC have been postulated as possible prognostic markers in pediatric AML with normal karyotype. Pretreatment blood samples from 47 cytogenetically normal AML patients were analysed for BAALC and ERG expression using real time RT-PCR. The patients were dichotomized at BAALC and ERG mean expression into low and high expression based on the median expression as cutoff. BAALC showed high expression in (24/47; 51.1 %) of patients and ERG high expression was detected in (22/ 47; 46.6 %). With follow-up for 1 year, patients with high BAALC and high ERG had inferior EFS (P = 0.001, P = 0.017 respectively), overall survival (P = 0.001, 0.08 respectively), and low rates of induction remission (P = 0.001, P = 0.0017 respectively) as compared to those with low expression. Also there was significant positive association between high expression of BAALC; ERG and FLT-ITD mutations (P = 0.016; P = 0.007 respectively). Multivariable analysis confirmed that high BAALC expression is an independent risk factor for EFS [HR for EFS 1.9(1.04-3.46) P = 0.037]; and OS [HR OS 1.55(1.7-3.36) P = 0.03]. In conclusion: Over expression of BAALC could predict adverse clinical outcome and may define important risk factor in cytogenetically normal pediatric AML.

show abstract

Section: Introductionmentioning

confidence: 99%

The Prognostic Relevance of BAALC and ERG Expression Levels in Cytogenetically Normal Pediatric Acute Myeloid Leukemia

Aref

Khodary

Zeed

et al. 2014

Indian J Hematol Blood Transfus

View full text Add to dashboard Cite

show abstract

“…Subsequent displacement of the fluorine from this common intermediate using a variety of secondary amines gave rise to the substituted benzamides 2 and 5−18 in high overall yields. In several cases (13,15,17), an additional step involving Boc deprotection was required.…”

mentioning

confidence: 99%

Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction

Bolshan

Getlik

Kuznetsova

et al. 2013

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (K dis = 7 μM), leading to identification of more potent antagonist 47 (K dis = 0.3 μM). KEYWORDS: WDR5, MLL, SET1 methyltransferase complex, peptide binding site, small molecule antagonists T he SET1-family of human histone methyltransferases (SET1A, SET1B, MLL1, MLL2, MLL3, and MLL4) contribute to active chromatin via mono-, di-, and trimethylation of lysine 4 on histone H3. 1−3 MLLs are S-adenosyl methionine (SAM) dependent lysine methyltransferases that work optimally when in complex with other components; WDR5 (WD40 repeat protein 5), RbBP5 (retinoblastomabinding protein-5), ASH2L (absent small homeotic disks-2-like), and DPY-30 (WRAD). 4 WDR5 has been shown to be essential for complex integrity and for fully activating MLL methyltransferase function. 5−7 In the peptide-bound structure, WDR5 adopts a donutshaped WD40-repeat fold with a deep central cavity that normally accommodates an arginine side chain of interacting peptides. 8 WDR5 binds to the "WDR5 INteracting" (WIN) motif of MLL1 through the peptidyl arginine-binding cleft. 8−12 A crystal structure of WDR5 in complex with MLL1 WIN peptide revealed the critical role of arginine 3765 of MLL1 in complex formation. 9 A similar interaction has been reported for WDR5 and the WIN region of all SET1 family lysine methyltransferases, with reported K D values of 1.13, 0.16, 2.03, 0.03, 0.26, and 0.10 μM for MLL1-4, SET1A, and SET1B WIN peptides, respectively. 13 Although there is significant divergence in the amino acid sequences of WIN motifs close to the critical arginine residue, the plasticity of the WDR5 arginine binding pocket allows such an interaction with the WIN motifs of all MLLs. 13 MLLs have been reported to be essential for embryonic development and biological processes 14−17 and have been widely implicated in a variety of cancers. 18−22 As almost all MLLs show minimal or no activity in the absence of the complex components (WDR5 in particular), 13 identifying WDR5−MLL interaction antagonists has been proposed as a potentially selective alternative to active site directed inhibitors of MLL methyltransferase activity. Such antagonists could serve as a starting point for the development of potential therapeutics to treat MLL-rearranged leukemias or other related cancers. 23 Recent reports detailing the use of short arginine contain...

show abstract

Section: Réarrangements V(d)j Du Tcr Et Différenciation Des Thymocytesunclassified

“…Les facteurs de transcription à homéodomaine sont généralement impliqués dans l'organogenèse, la maintenance de l'homéostasie des tissus. Ils participent au contrôle de multiples fonctions cellulaires dont la croissance, la prolifération et l'apoptose [5] cellules restent ainsi dépendantes du blocage de maturation dont la levée semble incompatible avec leur survie, et ce malgré l'accumulation de nombreux autres évènements oncogé-niques habituellement présents dans ces hémopathies. Il n'est pas inconcevable non plus qu'un signal TCR fort dans une cellule bloquée au stade de la -sélection soit interprété comme un signal de sélection néga-tive thymique et provoque l'apoptose.…”

Section: Réarrangements V(d)j Du Tcr Et Différenciation Des Thymocytesunclassified

“…Un métabolisme primitif nécessite égale-ment que ces polymères soient capables de se replier dans des structures tertiaires stables ayant des fonctionnalités élaborées telles que la reconnaissance d'un ligand et la catalyse [5]. Parmi les systèmes étudiés, l'acide nucléique (3', 2')--L-thréose (ANT, Figure 1) pourrait jouer le rôle de précur-seur de l'ARN en raison de sa simplicité structurale -son squelette est constitué de thréoses qui ont un carbone de moins que les riboses de l'ARN -et de sa capacité à former des structures hélicoïdales stables avec des brins complémentaires d'ANT ou d'ARN [6][7][8].…”

Section: Cbfa2unclassified

See 1 more Smart Citation

Mécanisme d’action des oncogènes à homéodomaine TLX dans les LAL-T

Asnafi

Ferrier

2012

Med Sci (Paris)

View full text Add to dashboard Cite

> Parmi les hémopathies, les leucémies aiguës lymphoblastiques T (LAL-T) représentent 15 à 25 % de l'ensemble des LAL et se caractérisent par un phénotype d'arrêt de maturation à un stade précoce de la différenciation lymphoïde T. Ces affections représen-tent ainsi un groupe hétérogène de leucémies aiguës dont le trait commun est un blocage de la différenciation cellulaire à un stade donné de la maturation thymique [1,2]. Leur pronostic, bien que nettement amélioré grâce aux progrès thérapeutiques récents, reste dans l'ensemble relativement médiocre, les taux de survie avoisinant 50 % à 5 ans chez l'adulte et environ 70 à 80 % chez l'enfant [3]. Dans ce contexte, l'identification de biomarqueurs susceptibles d'être utilisés pour la mise au point de thérapies ciblées représente un enjeu particulièrement important. Réarrangements V(D)J du TCR et différenciation des thymocytesL'oncogenèse des LAL-T est multigé-nique, avec coexistence de plusieurs dérégulations oncogéniques chez le même patient [4]. Parmi les sousgroupes identifiés, figure l'important groupe TLX marqué par la surexpression des oncogènes TLX1 ou TLX3. Ces gènes se caractérisent par la pré-sence d'une séquence d'ADN particulière, appelée homeobox, qui code pour un domaine protéique conservé ou homéodomaine, de structure hélice-tour-hélice. Cette structure a la propriété de se lier à l'ADN et d'interagir avec des protéines partenaires. Les facteurs de transcription à homéodomaine sont généralement impliqués dans l'organogenèse, la maintenance de l'homéostasie des tissus. Ils participent au contrôle de multiples fonctions cellulaires dont la croissance, la prolifération et l'apoptose [5]

show abstract

Hox genes in hematopoiesis and leukemogenesis

Cited by 432 publications

References 139 publications

The Prognostic Relevance of BAALC and ERG Expression Levels in Cytogenetically Normal Pediatric Acute Myeloid Leukemia

The Prognostic Relevance of BAALC and ERG Expression Levels in Cytogenetically Normal Pediatric Acute Myeloid Leukemia

Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction

Mécanisme d’action des oncogènes à homéodomaine TLX dans les LAL-T

Contact Info

Product

Resources

About