[1303] Expression of Notch Pathway Proteins in Lymphoblastic Leukemia/Lymphoma

W Chen, P Kapur, T Isaacson, D Rakheja. UT Southwestern Medical Center, Dallas, TX

Background: The Notch proteins are a family of transmembrane receptors consisting of Notch1, Notch2, Notch3, and Notch4. Binding of a Notch protein to its cognate ligand (Jagged1) leads to its regululated proteolysis by γ-secretase, releasing the Notch intracellular domain (NICD). The NICD translocates to the nucleus and joins a transcriptional activation complex, stimulating the expression of a number of key genes involved in cell growth and proliferation. While activating mutations in Notch1 are found in 50-60% of T-lymphoblastic leukemia/lymphoma (LBL), expression of the Notch proteins and Jagged1 has not yet been well characterized in both T- and B-LBL and was the focus of this study.
Design: Immunohistochemical analysis (IHC) was performed using antibodies against Notch1 (Chemicon), Notch2 (Abcam), Notch3 (Abcam), Notch4 (Santa Cruz), and Jagged1 (Abcam) on sections of a tissue microarray consisting of 28 cases of pediatric LBL (24 of B- and 4 of T-LBL, respectively). Staining was evaluated on a scale of 0 (negative) to 3 (intensely positive in most cells), and the pattern of immunoreactivity was appraised.
Results: Strong expressions of Notch2 and Jagged1 with nuclear immunoreactivty (NI) were identified in 92 and 86% of cases, respectively. Expression of Notch1 was variable and relatively weak compared to Notch2, although 74% of the positive cases had NI pattern. Notch 3 expression was weaker and in a smaller number of cases, and none of cases had NI pattern but showed cytoplasmic staining. Notch4 was not expressed. There was no difference in expression between T- and B-LBL.

Expression of Notch Pathway Proteins by IHC in LBL
ResultsNotch1Notch2Notch3Notch4Jagged1
0001702
122402
2251605
30250019
Positive/total cases100%100%37%093%
NI*74%100%0%0100%
*, Nuclear immunoreactivity within the positively stained cases.


Conclusions: Both T- and B-LBL constitutively express Notch pathway proteins, Notch1, Notch2 and Jagged1. The novel findings in this study are strong and nearly uniform nuclear expressions of Notch2 and Jagged1, suggesting that this pathway may play an important role in LBL pathogenesis. In addition, an autocrine/paracrine Notch-Jagged1 signaling loop might be operative, and Jagged1 may also function as a transcription factor given its nuclear immunoreactivity. These findings support the potential benefit of therapeutic interventions with Notch inhibitors in patients with LBL.
Category: Hematopathology

Tuesday, March 23, 2010 1:00 PM

Poster Session IV # 167, Tuesday Afternoon

 

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