5. Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) is characterized by the presence of Philadelphia chromosome t(9;22)(q34;q11) (BCR-ABL1), for which targeted therapy with tyrosine kinase inhibitors (TKI) have revolutionized the treatment of CML. In an effort to define genetic lesions that cooperate with BCR-ABL1 to transform to Philadelphia chromosome positive acute leukemia, Mullighan et al. [65] studied 304 cases of ALL, including 23 CML cases with a 250K Affymetrix SNP array, and found only 0.47 copy number alterations per case in chronic phase CML (range 0–8), which suggested that chronic phase CML is genomically stable and BCR–ABL1 is sufficient to induce CML. However, a separate study by Khorashad et al. [66] on 10 chronic phase CML patients with high resolution 2.1 million oligonucleotide array comparative genomic hybridization (CGH) showed an average of 53 CNAs per patient (range: 4–166) with majority being amplifications. The difference in CNAs detected by the two techniques is most likely due to the marked difference in resolutions of the arrays. In Mullighan’s study, IKZF1 was deleted in CML lymphoid blast phase, but not in CML chronic phase [65]. The IKZF1 encodes IKAROS which is an essential transcription factor for normal lymphoid development. Deletion of IKZF1 results in monoallelic, expression of dominant-negative form, or loss of expression of IKAROS. Deletion of PAX5 and CDKN2A/B, together with loss of IKFZ1 in lymphoid but not myeloid blast phase of CML indicates that these genes play important role in the transformation of CML to lymphoid blast phase of CML [32]. A subset of the CML patients is resistant to TKI therapy, mainly due to BCR-ABL1 mutations or amplification. In a study to identify genetic alterations in 45 TKI-resistant CML by 250K SNP array, Nowak et al. [67] found recurrent submicroscopic alterations, including aUPD in chromosomes 1, 8, 9, 17, 19, and 22. Recurrent deletions of IGLC1 locus on chromosome 22 were identified in three patients with previous blast crisis, suggesting dedifferentiation into immature progenitors as a possible mechanism of TKI resistance.