Notch/HES1 and PARP1 Protein Co-Expression among B-Lymphoblastic Leukemia/Lymphoma Patients (pts) Predicts Good Prognosis
Adnan Mansoor, Payam Pournazari, Michelle Dean, Sarah-Joy Haggstrom, Brant Pohorelic, Farid Kosari, Meer-Taher Shabani-Rad, Jay Patel, Iwona Auer, Xiu Yan Jiang, Doug Demetrick, Nizar Bahlis, Douglas Stewart, Alexander C Kilmowicz. University of Calgary, Calgary, AB, Canada; Tom Baker Cancer Centre, Calgary, AB, Canada
Background: Notch signaling provides a highly conserved pathway that regulates lymphocyte cell lineage and plays contrasting roles (oncogene & tumor suppressor) in T- and B-cell leukemias. HES1 is a downstream target of Notch/CSL and affects growth and survival in B-cell ALL (B-ALL). Typically HES1 is a transcriptional repressor; but may lead to transactivation of some genes. Recently, HES1 associated transactivation of PARP1 has been reported in B-ALL cell lines (Kannan et al, Blood,2011). PARP1 is a ubiquitous nuclear protein implicated in critical stress-related functions such as DNA repair and apoptosis. We studied HES1 and PARP1 protein expression by routine IHC combined with digital image analysis in B-ALL pts and related their expression with survival and other known prognostic factors.
Design: Diagnostic (WHO-2008) BM biopsy tissue (FFPE) was used to create TMA (triplicate cores, 0.6 mm). Sections (4 µM) were stained with various markers (CD34,PARP1, HES1, CD10, Tdt) according to standard protocol. Stained TMA slides were scanned on an Aperio Scanscope XT and digital imaging software (Definiens Tissue Studio 2.1) was used for stain scoring utilizing the manufacturer's nuclear positivity algorithms (as for ER/PR). X-tile software and bivariate regression analysis were used to identify cut-points (HES1, 60% & PARP1, 40% maximum positivity index scores). SPSS software was used for statistical analysis.
Results: 51 pts between ages 2-85 yrs (Median 49 yrs; Mean 53 yrs; M:F 1:1) were included (34 Pre B-ALL, 17 B-ALL). 46/51 (90%) pts had informative histospots. HES1 positivity was noted in 29/46 (63%) pts while PARP1 was positive in 30/46 (65%). 5 yr overall survival in HES1+ group was 55% (16/29) compared to 29% (5 of 17) in HES1- group (p=0.0281). HES1+PARP1 positivity was seen in 20/46 (54%). Co-expression of HES1+PARP1 provided higher survival benefit (71% vs 27%; p 0.0289; PPV 0.71 & NPV 0.76). Prognostic value of HES1+PARP1 was significant in men (p=0.003) compared to women (p=0.989). Predictive value of HES1/PARP1+ was seen primarily among pts with normal cytogenetic (p=0.006) compared with pts with various translocations (p=0.993).
Conclusions: Our data, suggest that HES1, associates with good prognosis in B-ALL, further enhanced by interactions with PARP1 protein expression. HES1+PARP1 is highly significant of better OS in pts with normal cytogenetics. Its good prognostic value is unaffected by presence of other prognostic markers like gender or translocations (9;22).
Monday, March 19, 2012 2:00 PM
Platform Session: Section C, Monday Afternoon