Blastic transformation of BCR‐ABL1 positive chronic myeloid leukaemia through acquisition of CBFB‐MYH11 and mutant KIT

Abstract

Blastic transformation of BCR-ABL1 positive chronic myeloid leukaemia through acquisition of CBFB-MYH11 and mutant KIT Chromosomal aberrations in addition to BCR-ABL1 at diagnosis of chronic myeloid leukaemia (CML) in chronic phase (CP-CML) occur in~5-12% of patients. 1-3 Progression to blast phase (BP) is accompanied by genetic evolution with concomitant resistance to tyrosine kinase inhibitor (TKI) treatment. 3 Among aberrations described in BP-CML but very rarely in CP-CML is the acute myeloid leukaemia (AML) defining inv(16)/t(16;16) leading to CBFB-MYH11. 4 CBFB-MYH11-positive AML is associated with mutations in exons 8 or 17 of the KIT gene, which occur in~30% of patients and likely confer an adverse prognosis. 5 We report a patient with BCR-ABL1_p210-positive CP-CML with co-occurrence of CBFB-MYH11_A at initial diagnosis, which progressed to myeloid BP-CML under treatment with nilotinib after acquiring three different in-frame indel mutations in exon 8 of KIT.

Secondary fusion proteins as a mechanism of BCR::ABL1 kinase‐independent resistance in chronic myeloid leukaemia

“…Previous research has identified several changes that occur in the advanced phases of CML, including the appearance of secondary fusion proteins, which may contribute to disease progression. Some such fusions involve genes such as RUNX1 , 4,5 CBFB , 6,7 and KMT2A 8 that are associated with different cancers. However, the significance of secondary fusions and their ability to mediate resistance remains unclear.…”

Discovering Genotype Variants in an Infant with VACTERL through Clinical Exome Sequencing: A Support for Personalized Risk Assessment and Disease Prevention

“…MYH11 has one missense heterozygous and one heterozygous splice region variant. It encodes for Myosin-11 and is mainly involved in muscle contraction; however, when altered, it may contribute to intestinal [49], gastric, and colorectal [50] cancers and acute myeloid leukemia [51]. PCM1 carries a heterozygous missense mutation of two close nucleotides.…”

Blast phase of chronic myeloid leukemia with concurrent BCR::ABL1 and SET::NUP214: A report of two cases

“…The most common additional cytogenetic abnormalities include trisomy 8, an extra copy of the Ph chromosome, chromosome 3 aberrations, −7/del(7q), −Y, i(17), trisomy 21, and trisomy 19 3–5 . However, the additional fusion gene was rarely reported such as CBFB::MYH11 in CML‐BP 6,7 …”

“…The low levels at initial diagnosis precluded its detection by multiplex RT‐PCR. It has been reported that a low level of CBFB::MYH11 (0.204%) was detected in a patient with CML‐CP at the initial diagnosis 7 . It is necessary to make Q‐PCR, a highly sensitive tool, as a routine detection method for the initial diagnosis of CML‐CP and disease transformation.…”

“…[3][4][5] However, the additional fusion gene was rarely reported such as CBFB::MYH11 in CML-BP. 6,7 To the best of our knowledge, there was no literature reporting simultaneous occurrence of BCR::ABL1 and SET::NUP214 rearrangement in CML. Meanwhile, there is not sufficient information on the clinical characteristics and treatment outcomes of patients carrying the SET::NUP214 fusion gene.…”