Expression of Notchl and Jaggedl Proteins in Acute Myeloid Leukemia Cells

Abstract

Cell fate of hematopoietic progenitors is regulated by interaction between Notch proteins on progenitors and Notch ligands such as Jagged1 on stromal cells. Since acute myeloid leukemia (AML) originates from dysregulated hematopoietic progenitors, some abnormalities in the Notch-Jagged system may exist in AML cells. As the first step to clarify this, we examined the expression of Notch1 and Jagged1 proteins in eight AML cell lines and 15 fresh AML samples by immunoblotting. In the Notch1 protein, two bands, a 300 kDa band and a 120 kDa band, which appeared to be a full-length protein and a transmembrane fragment, respectively, were recognized in five AML cell lines and six fresh samples. In addition, three of the five cell lines showed a 110 kDa fragment, which appeared to be from an intracellular domain, namely an active form. One cell line showed aberrant sized fragments, which suggested a structural abnormality. Jagged1 protein was recognized in six cell lines and six fresh samples. In four cell lines and four fresh samples, both Notch1 and Jagged1 proteins were observed. In these cells, Notch1 and Jagged1 proteins may interact among themselves. We showed that Notch1 and Jagged1 proteins are widely expressed in AML cells. We hypothesize that some abnormalities in the Notch-Jagged system which cause the excessive self-renewal and the block of differentiation, may be involved in the abnormal proliferation of AML cells.

Mouse Fbw7/Sel-10/Cdc4 Is Required for Notch Degradation during Vascular Development

“…Deregulated expression of wild-type Notch or of Notch ligands or downstream targets has been detected in cervical, lung, colon, head and neck, and renal carcinomas (54 -57), acute myeloid leukemia (58), and Hodgkin's and large cell lymphomas (59). Notch1 was recently shown to be a downstream effector of oncogenic Ras, and down-regulation of Notch1 in Ras-transformed human cells was sufficient to abolish key elements of the neoplastic phenotype in vitro and in vivo (60).…”

p53 regulates thymic Notch1 activation

“…Loss or mutation of p53 is common in many types of human cancer, including a mutation rate of 13% in lymphoid malignancies (reviewed in [3]). A variety of studies have also linked cell survival and, potentially, cancer development with Notch expression [42][43][44][45][46][47][48][49][50], (reviewed in [9]). The Trp53 -/-mice develop tumors, primarily lymphomas, by approximately 4 months of age [4], which may partially be due to the increased N IC expression observed in Trp53 -/-thymocytes.…”

Characterization of tissue specific expression of Notch-1 in human tissues

“…It is well established that constitutive overexpression of active Notch-1, -2 or -3 predisposes to T-cell malignancies (Aster and Pear, 2001). Among hematopoietic malignancies, acute myeloid leukemia (Tohda and Nara, 2001) as well as Hodgkin and largecell anaplastic lymphomas (Jundt et al, 2002) have been shown to overexpress Notch-1, while B-cell CLL has been shown to overexpress Notch-2 (Hubmann et al, 2002). Moreover, Jagged-1/Notch-1 interactions have been shown to induce proliferation and survival in Hodgkin and large-cell anaplastic lymphomas (Jundt et al, 2002).…”