New type of Bcr/Abl junction in Philadelphia chromosome-positive chronic myelogenous leukemia

Abstract

A new and rare type of Bcr/Abl junction between exon C3 of the 3′ portion of the Bcr gene and Abl exon 2 has been identified in the leukemic cells of two Ph1-positive chronic myelogenous leukemia patients in chronic phase. This is the fourth type of Bcr/Abl junction so far identified in Ph1-positive hematologic malignancies and is a consequence of an unusual breakpoint position on chromosome 22 that falls approximately 20 kb downstream of the major breakpoint cluster region (bcr) of the Bcr gene. The new hybrid mRNA is 540 base pairs (bp) longer than that expressed by the K562 cell line and could codify for a Bcr/Abl protein carrying 180 additional aminoacids with respect to the larger P210 protein so far identified. The hematologic phenotype expressed by the two patients carrying this unusual type of Bcr/Abl rearrangement does not significantly differ from that commonly seen in chronic myelogenous leukemia.

Elevated platelet count features the variant type of BCR/ABL junction in chronic myelogenous leukaemia

“…To our knowledge, three other cases with BCR exon c3 fused to ABL exon 2 have been reported (Saglio et al, 1990;Wada et al, 1995). It remains unclear whether CML patients with this variant form of BCR/ABL protein have a different clinical manifestation from those with p210 BCR/ABL protein.…”

“…In one type, BCR exon 2 is fused to ABL exon 2 (b2-a2 type), and in the other, BCR exon 3 is fused to ABL exon 2 (b3-a2 type). Recently, two groups have reported three CML cases with a variant type of BCR/ABL junction (Saglio et al, 1990;Wada et al, 1995). The breakpoint in this type of rearrangement occurs further downstream of M-bcr, between BCR exon c3 and exon c4 (Groffen et al, 1984;Lifshitz et al, 1988).…”

Prevalence and outcomes of uncommon BCR‐ABL1 fusion transcripts in patients with chronic myeloid leukaemia: data from a single centre

“…Thus far, over 50 CML patients with the e19a2 transcript have been reported, and 19 of them received TKI therapy, but the responses and outcomes on imatinib therapy were ambiguous (Saglio et al , ; Ikeda et al , ; Sazawal et al , ). In the current study, we identified 33 patients with the e19a2 transcript, who had significantly higher probability of high Sokal risk scores at diagnosis and significantly lower probabilities of CCyR, MMR, EFS and PFS than patients with common BCR‐ABL1 transcripts in response to frontline imatinib therapy, whereas 5 patients with the e19a2 transcript seem to have better responses to second generation TKIs.…”

“…The BCR‐ABL1 fusion gene is the molecular hallmark of chronic myeloid leukaemia (CML) (Lugo et al , ). More than 95% of CML patients have the typical P210‐encoding BCR‐ABL1 fusion gene resulting from either an e13a2 (b2a2) or e14a2 (b3a2) junction, and cases with uncommon BCR‐ABL1 junctions, such as e19a2 and e1a2, are rare and may result in BCR‐ABL1 being undetectable by routine polymerase chain reaction (PCR) (Saglio et al , ; Selleri et al , ; Melo, ). Regular monitoring of BCR‐ABL1 transcript levels by real‐time quantitative PCR (RQ‐PCR) has become an integral part of routine clinical management of CML in the tyrosine kinase inhibitor (TKI) era (Hughes et al , ); therefore, identifying the junction characteristics of the BCR‐ABL1 fusion gene is necessary for performing appropriate RQ‐PCR.…”

Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation

“…The µ‐BCR breakpoint connects exon 19 of BCR with exon 2 of ABL1 giving rise to the e19a2 transcript, which has been associated with a mild CML phenotype , defined as Ph + chronic neutrophilic leukemia (Ph + ‐CNL). Ph + ‐CNL is an uncommon myeloproliferative disorder, which shows a more indolent course than classical CML .…”