7. Myelodysplastic/Myeloproliferative Neoplasms
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are characterized by the presence of features of both MDS and MPN. Chronic myelomonocytic leukemia (CMML) is the most common form of MDS/MPN and characterized by persistent monocytosis, dysplasia, and transformation to acute myeloid leukemia. SNP Array 6.0 identified genomic alterations in 60% of patients with CMML with cryptic CN-LOH in 71% and microdeletions in 45% cases [75]. CN-LOH was frequent on 7q harboring EZH2, 11q harboring CBL, and 4q harboring TET2. The presence of multiple chromosomal defects detected by SNP array was associated with a worse overall survival by univariate analysis [75]. In a separate study, UPD occurred in 48% of CMML by 250K SNP array analysis, with the most frequently affected chromosomal region in 11q harboring proto-oncogene c-CBL [76]. All patients with UPD 17q and UPD 4q were found to have CMML or M5 primary AML. These studies indicated that CMML is genetically heterogeneous with different pathways to a common disease phenotype, and CBL mutations may activate the RAS pathway and aberrant pSTAT5 activation in CMML. A recent study suggested that abnormal SNP array lesions were associated with an inferior complete and partial remission rate, and worse overall survival when compared with patients without SNP lesions after decitabine therapy [77]. This finding, if confirmed, would certainly help better prognostic stratification and treatment of CMML patients.
Juvenile myelomonocytic leukemia (JMML) is a rare clonal hematopoietic disorder of childhood characterized by monocytosis and loss of function of neurofibromatosis 1 (NF1) or somatic mutations of genes in RAS/MAPK pathway. Flotho et al. [78] first applied SNP array on 16 cases of JMML with normal karyotype and identified large regions of UPD on chromosome 17 spanning approximately 55 Mb, which contained the locus of the NF1 tumor suppressor gene on 17q11.2, in four of five patients with JMML and NF1, but not in other cases without NF1. Inactivating NF1 lesion on both alleles was found by mutational analysis in each case. This study indicates that 17q UPD with homozygous loss of normal NF1 plays a critical role for the pathogenesis of JMML in NF1 patients.