A novel insertion mutation of K294RGG within BCR-ABL kinase domain confers imatinib resistance: sequential analysis of the clonal evolution in a patient with chronic myeloid leukemia in blast crisis

Abstract

BCR-ABL kinase domain mutations were sequentially analyzed in a patient with chronic myeloid leukemia (CML) who exhibited repeated B-lymphoid blast crisis (CML-BC) during treatment with imatinib and dasatinib. We first identified five mutant BCR-ABL clones: Y253H, G250E, F311L, F317L and K294RGG, which was generated by two-nucleotide mutations and six-nucleotide insertion, at the third BC during the imatinib treatment, and retrospectively found that three of them (Y253H, G250E, K294RGG) were already present at the second BC. The in vitro analysis using K294RGG mutant BCR-ABL-expressing 32D cells revealed that K294RGG mutation was imatinib resistant but dasatinib sensitive. Consistent with the in vitro data, the clone with K294RGG mutation was eliminated by the dasatinib treatment in this patient. During the imatinib treatment, several mutant clones emerged and expanded, while additional mutations on the same allele were not acquired. However, after the dasatinib treatment, wild-type BCR-ABL clone disappeared and T315I or F317L mutation was acquired in G250E and Y253H mutant clones on the same allele without the emergence of each sole mutant clone. Cytogenetic and immunoglobulin heavy chain gene rearrangement analysis revealed that all mutant clones that appeared in this patient might be derived from the same CML clone.

K356dup – an in‐frame insertion in the BCR‐ABL gene in an imatinib‐resistant chronic myeloid leukemia

“…The only other functional BCR-ABL KD insertion mutant in CML had been reported in early 2011 by team from Nagoya [11]. Their publication described a patient with four consecutive blast crises, harboring multiple point mutations along with K294RGG.…”

Cancer stem cell: A rogue responsible for tumor development and metastasis

“…[37][38][39] The clonal evolution model claims that normal cells mutate and generate abnormal offspring that also mutate, forming a mass of genetically varied cancer cells. [40] At least two hits of oncogenic mutation may be required. [41,42] Practically, clonal evolution as a mechanism appears to underlie CSC development.…”

Imatinib failure and response to dasatinib in a patient with chronic myeloid leukemia in blast crisis and a novel, nine-nucleotide BCR-ABL insertion mutation

“…7 A p.K294R_insGG mutation recently was identified in a patient with blast crisis CML and imatinib resistance. 8 Thus, more complex mutations such as insertion of several nucleotides adjacent to codon K294 that mediate strong resistance might require genetic instability as it is present in blast crisis. Mutations involving the ABL SH3-binding domain including K294 insertion mutations might retain sensitivity to dasatinib, as observed in our patient.…”