The Expression of LI-Cadherin in Bone Marrow Is Correlated with Clinical Outcome in Children with Acute Lymphoblastic Leukemia at First Relapse.

Abstract

Liver and Intestine (LI)-cadherin, also termed cadherin-17, is a calcium ion dependent cell-cell adhesion molecule that is highly expressed in the intestinal epithelia but not in the upper gastric tract. Although LI-cadherin is not found in the healthy gastric mucosa, it is ectopically expressed in gastric metaplasia and adenocarcinomas. Recently it was revealed that LI-cadherin expression correlates with gastric cancer progression and lymph node metastasis. In mice LI-cadherin was found to be expressed by B cell progenitor cells. Whether LI-cadherin expression is also linked to the development and progression of malignant hematologic diseases is not known.In this study, we for the first time showed that LI-cadherin can be detected in several leukemic B-cell lines like Raji, MHH, Nalm6, Z33, REH, and T-cell lines Jurkat, Molt3, Molt4, Molt16 by western bloting and RT-PCR. We subsequently analyzed the expression of LI-cadherin in leukemic bone marrow (BM) slide samples and correlated its impact on the clinical outcome in 119 children with first relapse acute lympnoblastic leukemia (ALL) enrolled in the Berlin-Frankfurt-Münster ALL relapse trial. LI-cadherin expression could be detected in 24 of 119 BM samples (20.2%) using immunofluorescence staining. The frequencies of LI-cadherin in B-cell progenitor (BCP)-ALL and pre-T/T-ALL were 18.4% (19/103) and 31.3% (5/16), respectively. Within BCP-ALL relapses, the maturation-linked expression of LI-cadherin was seen in 22.9% of more mature pre-B (n = 35) than in 17.2% of common (n = 64) or 0% of pro-B (n = 4) leukemic cells. Analysis was confined to BCP lineage to avoid biases related to immunophenotype. Most notably, the probability of survival (pSRV) at 5 years was significantly worse for children with first relapse BCP-ALL who expressed LI-cadherin in BM samples (n = 19) compared with patients who had no expression of LI-cadherin (n = 84) (pSRV: 0.71±0.06 vs. 0.35±0.17; p<0.05). Furthermore, the expression of LI-cadherin was also observed in BM stromal cells which are assumed to support leukemic cell growth and survival.These results indicated that the expression of LI-cadherin in BM represents a negative prognostic factor for children with first relapse ALL. Since stromal cells also express LI-cadherin, they could bind to LI-cadherin expressing leukemic cells and thus modulate disease progression and/or response to therapy.