Gene amplification in leukemia is relatively rare, mostly reported for the MLL and CMYC oncogenes. However, MET amplification has not been reported in leukemia. Here, we report the first case of MDS with MET amplification in the form of a ring chromosome. The patient was a 52-year-old male who initially presented with shortness of breath and fatigue during the latter part of December 2014. A CBC was performed at this time and revealed marked leukopenia, anemia, and thrombocytopenia. Upon arrival to our facility, assessment of bone marrow biopsy and aspirate revealed dysplastic changes consistent with the diagnosis of myelodysplastic syndrome (MDS), classified as RAEB-2. Chromosomal analysis at that time revealed at least two unrelated clones; the dominant clone presented with multiple unbalanced chromosomal rearrangements, and extreme karyotypic heterogeneity. However, the most notable chromosomal aberrations were additional genetic material on chromosomes 7q, 16p and 19p, a large ring that appeared to be derived from chromosome 7, and an inversion of Xp. Clone 2, was a minor clone and showed 5q and 20q deletions, the classic abnormalities for MDS. FISH demonstrated deletions of EGR1/5q31 and 20q12 in 8-12% of cells, but unexpectedly amplification of the 7q31 region was noticed in 60% of cells. The FISH probe, D7S486/7q31, spans a region of 306kb, which contains several tumor suppressor genes such as MDFIC, TES, CAV1. The closest candidate oncogene to D7S486 region at 7q31 is the MET gene. Therefore, MET/7q31.2 probe was hybridized to the same specimen that confirmed an amplification of MET oncogene. In metaphase cells, the amplified signals are located on the ring chromosome which lacks a centromere 7 signal (Figure 2). The MET gene encodes a tyrosine kinase receptor for the hepatocyte growth factor (HGF). Whereas the physiological expression of MET is essential for wound healing and embryonic development, aberrant overexpression of MET results in up-regulation of cell proliferation, motility, migration, invasion, and survival. MET MET activating mutations and gene amplification have been identified in a variety of solid tumors including, gastric, pharynx, colon, lung, and breast cancer. Further studies have shown that inhibition of MET signaling pathways has led to inhibition of growth, migration and invasion. For these reasons MET has become a valuable target for cancer therapy and several drugs targeting MET and its ligand HGF are being evaluated in clinical trials in various cancers. The MET gene is also overexpressed in hematological malignancies. The most recent studies on multiple myeloma showed that the HGF/MET pathway is constitutively active in plasma cells of myeloma patients and it confers multidrug resistance. These findings were also true for acute myeloid leukemia (AML). Studies of samples taken from AML patients and cell lines revealed that MET is activated in leukemic cells as a result of aberrant autocrine signaling by HGF, and inhibition of this autocrine activation loop would inhibit the growth and survival of these cells. Other genes of significance within the region of chromosome 7q31 include MDFIC, TFEC, TES, CAV-1, CAV-2, and ST7. These genes have been implicated in various malignancies but their role has not yet been fully elucidated. TES, CAV-1, CAV-2, and ST7 are considered candidate tumor suppressors implicated in numerous malignancies. MDFIC, also known as HIC, is frequently deleted in myeloid malignancies. TFEC is a member of the microphthalmia family of transcription factors whose dysregulation may have a role in renal cell carcinoma, melanoma, and sarcoma. Despite aggressive therapy, our patient never achieved remission, and he died from disease progression shortly after transplant. The complex karyotype as well as MET amplification certainly contributes to the dismal sequence of the disease. Therapeutic agents targeting the MET pathway may help improve patient survival. |
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