Page 151 - 2018_12-Haematologica-web

Trisomy 12 CLL
Table 3. Ingenuity Pathway Analysis of differentially-regulated canonical pathways.
+12 vs. del(13q) Pathway
Phospholipase C signaling
Integrin signaling
Regulation of actin-based motility by Rho Remodeling of epithelial adherens junctions Protein kinase A signaling
Role of BRCA1 in
DNA damage response
RhoGDI signaling
Fcg receptor-mediated phagocytosis in macrophages and monocytes Non-small cell lung cancer
signaling
Gαqsignaling
vs.: versus; S: Status of pathway compared to +12 CLL; A: activated; D: down-regulated.
atively small, our results are similar to those of previous studies.18,21-23 However, we found no differences in expres- sion of NOTCH1 or NOTCH1 target genes (e.g. HES1, DTX1, NRARP) between NOTCH1-mutated and unmutat- ed cases. Recently, Fabbri et al. analyzed NOTCH1 RNA expression in normal B-cell subsets and more than 100 PB CLL cases.12 They found that tonsillar naïve and memory B cells expressed NOTCH1, HES1, and MYC, while ger- minal center B cells were negative. Furthermore, about 50% of CLL cases that lacked NOTCH1 mutations expressed the active intracellular portion of NOTCH1. They describe a “NOTCH1 gene expression signature” that regulates critical B-cell processes, but is independent of NOTCH1 mutation.
Using pathway analysis, we identified canonical path- ways that are differentially regulated in +12 CLL com- pared to other subtypes; several converge on the BCR sig- naling pathway. One of the most highly activated path- ways was integrin signaling. Integrins are transmembrane receptors that mediate interactions between the extracel- lular matrix and actin cytoskeleton. Integrins enhance adhesion, which activates signaling pathways that regu- late migration, proliferation, cell survival, and other processes.24 B-cell receptor signaling is critical for CLL sur- vival and proliferation,25 and is enhanced through interac- tions between CLL cells and the microenvironment.26 Signals from the BCR are transduced by downstream kinases. Therapeutic agents that target Bruton’s tyrosine kinase (BTK) and the phosphatidylinositol-4,5-bisphos- phate 3-kinase catalytic subunit delta (PI3Kδ) are highly effective.27-29 Patients treated with kinase inhibitors experi-
+12 vs. del(11q)
S Pathway S
A TNFR2 D signaling
A HIPPO A signaling
A CD40 A signaling
A Death receptor D signaling
A TWEAK D signaling
D Sphingosine-1- A
phosphate
signaling
D TNFR1 D
signaling
A Signaling by A
Rho family GTPases
A Regulation of A
+12 vs. diploid
Pathway S
Ceramide D signaling
Non-small cell A
lung cancer signaling
NGF A
signaling
Integrin A
signaling
Pancreatic D
adenocarcinoma
Huntington disease A
signaling
Glioma A signaling
14-3-3-mediated D
signaling
IL-8 signaling A
+12 vs. all
Pathway S
Protein kinase A A signaling
Integrin A
signaling
Phospholipase A
C signaling
Ceramide A
signaling
Cell cycle: D
G1/S checkpoint regulation
Role of BRCA1 in D
DNA damage response
Insulin receptor A signaling
Huntington disease A
signaling
Remodeling of epithelial D
adherens junctions
actin-based motility by Rho
A RhoGDI
D HMGB1 A Glioma A
signaling
signaling signaling
ence a rapid rise in absolute lymphocyte count (ALC) due to egress of CLL cells from lymph nodes that declines slowly over approximately eight months.27-29 The magni- tude and duration of this transient redistribution lympho- cytosis varies with cytogenetic subtype; del(13q) patients with IGHV-mutated genes tend to experience prolonged lymphocytosis, while +12 patients show an attenuated rise in the ALC and a more rapid reduction to baseline.29,30 Redistribution lymphocytosis is likely a consequence of inhibition of CLL migration and adhesion due to disrup- tion of chemokine receptor and integrin signaling. For example, the BTK inhibitor ibrutinib abrogates adhesion of CLL cells to fibronectin, interfering with their ability to adhere to stromal cells.31
Recent studies indicate that +12 CLL express higher lev- els of several integrin proteins compared to other cytoge- netic subtypes.23,32 Similarly, we found overexpression of ITGAL and ITGB2 (which encode the αL and β2 chains of LFA-1), ITGA4 (which encodes the α4 chain of VLA-4), and ITGB7. We also observed overexpression of ITGB5 and vinculin (VCL). ITGB5 encodes the β5 integrin chain, a fibronectin receptor component. Increased ITGB5 may contribute to the attenuated redistributive lymphocytosis in +12 CLL by increasing adhesion to fibronectin and interfering with the CLL egress from lymph nodes. Vinculin stabilizes integrins at the immune synapse, the interface between the B cell and the antigen-presenting cell, and is critical for activation of BCR signaling.33 Thus, increased integrin-mediated signaling may promote reten- tion of +12 CLL cells within tissues. Alternatively, circu- lating +12 CLL cells may undergo more rapid apoptosis
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