Carta Acesso aberto Revisado por pares

CARMA1 is a novel regulator of T-ALL disease and leukemic cell migration to the CNS

2016; Springer Nature; Volume: 31; Issue: 1 Linguagem: Inglês

10.1038/leu.2016.272

ISSN

1476-5551

Autores

Sreenivasa Rao Oruganti, David J. Torres, Savannah Krebsbach, François Asperti-Boursin, Jeffrey L. Winters, Ksenia Matławska-Wasowska, Stuart S. Winter, Christina Halsey, Judy L. Cannon,

Tópico(s)

Immune Cell Function and Interaction

Resumo

Pediatric acute lymphoblastic leukemia (ALL) is the most common type of malignancy in children with 15% bearing markers for the T-lineage (T-ALL) and 20% of T-ALL patients still suffering disease relapse.Many genes are implicated in T-ALL disease, including Notch, and Notch mutations have been identified in a majority of T-ALL patients. 1Patients with T-ALL relapse with disease usually in the central nervous system (CNS). 2Despite the use of intrathecal therapy and cranial radiation, successful management of CNS disease continues to be problematic in T-ALL. 3Few molecules are known to be associated with T-ALL CNS disease including CCR7, a chemokine receptor normally expressed on naive T cells. 46][7] The involvement of chemokine receptors as well as other molecules regulating cell motility suggests that regulation of T-ALL cell migration is likely to have an important role in T-ALL.Cell signaling molecules that drive normal T-cell proliferation, such as PKCθ, can regulate T-ALL. 8PKCθ activates CARMA1 (also known as CARD11) bringing together Bcl10 and MALT1 leading to NF-κB activation. 9Although higher expression of CARMA1 has been seen in a small subset of T-ALL patients, little is known about how CARMA1 might regulate T-ALL. 10To study the potential role of CARMA1 in T-ALL disease, we used shRNA to knock down CARMA1 expression in the human CEM T-ALL cell line expressing luciferase and GFP (called CARMA1KD), with the level of knockdown ~50% (Supplementary Figure 1A).We transferred the CARMA1KD CEM cells into the immunodeficient NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ IL2RG (NSG) mice.Animals receiving CARMA1KD T-ALL cells survived significantly longer than animals receiving parental CEM cells (Figure 1a).We also used a Notch1-ΔE-induced mouse T-ALL model in which hematopoietic precursors from WT C57Bl/6 (called WT/WT Notch1ΔE ; labeled WT) or CARMA1 -/ -(WT/CARMA1 -/ -Notch1ΔE ; labeled CARMA1KO) animals were transduced with Notch1ΔE-GFP and develop T-ALL.Like the xenograft model, we found that WT/CARMA1 -/ -Notch1ΔE (CARMA1KO) animals survived significantly longer than WT/WT Notch1ΔE (WT; Figure 1b).We then asked whether CARMA1 is also involved in human T-ALL disease.Using microarray analyses from patient T-ALL cells, we compared CARMA1 expression in bone marrow (BM) cells from T-ALL patients with BM cells from a non-leukemia control population.CARMA1 expression was significantly higher in the T-ALL patients cells compared with non-leukemic cells (Figure 1c) and other tumor types including lung, liver and breast (Figure 1d).

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