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
ISSN1476-5551
AutoresSreenivasa 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
ResumoPediatric 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).
Referência(s)