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

Abstract

Summary Drug resistance in chronic myeloid leukaemia (CML) may occur via mutations in the causative BCR::ABL1 fusion or BCR::ABL1‐independent mechanisms. We analysed 48 patients with BCR::ABL1‐independent resistance for the presence of secondary fusion genes by RNA sequencing. We identified 10 of the most frequently detected secondary fusions in 21 patients. Validation studies, cell line models, gene expression analysis and drug screening revealed differences with respect to proliferation rate, differentiation and drug sensitivity. Notably, expression of RUNX1::MECOM led to resistance to ABL1 tyrosine kinase inhibitors in vitro. These results suggest secondary fusions contribute to BCR::ABL1‐independent resistance and may be amenable to combined therapies.

Loss of G0/G1 switch gene 2 (G0S2) promotes disease progression and drug resistance in chronic myeloid leukaemia (CML) by disrupting glycerophospholipid metabolism

“…Gene‐level expression data for G0S2 were obtained from primary CML patient MNCs isolated from either peripheral blood or BM and subjected to paired‐end 2×150 bp RNAseq using the Illumina HiSeq platform. 33 Samples were obtained following informed consent in association with Oregon Health & Science University IRB protocol #4422. Patient samples were separated by disease phase or TKI response: CP‐CML ( n = 53), accelerated phase CML (AP‐CML, n = 12), BP‐CML ( n = 13), newly diagnosed CP‐CML ( n = 21) and TKI‐resistant CML ( n = 42).…”

“…All TKI‐resistant CML patient samples had BCR::ABL1 kinase‐independent resistance, defined by loss of a molecular and/or cytogenetic response to one or more TKIs without the presence of an explanatory BCR::ABL1 kinase domain mutation. 33 Gene expression analyses using publicly available data are described in Supporting Information.…”

“…Cell line RNA sequencing (RNAseq) is described in Supporting Information (GSE171945). Gene‐level expression data for G0S2 were obtained from primary CML patient MNCs isolated from either peripheral blood or BM and subjected to paired‐end 2×150 bp RNAseq using the Illumina HiSeq platform 33 . Samples were obtained following informed consent in association with Oregon Health & Science University IRB protocol #4422.…”

“…Patient samples were separated by disease phase or TKI response: CP‐CML ( n = 53), accelerated phase CML (AP‐CML, n = 12), BP‐CML ( n = 13), newly diagnosed CP‐CML ( n = 21) and TKI‐resistant CML ( n = 42). All TKI‐resistant CML patient samples had BCR::ABL1 kinase‐independent resistance, defined by loss of a molecular and/or cytogenetic response to one or more TKIs without the presence of an explanatory BCR::ABL1 kinase domain mutation 33 . Gene expression analyses using publicly available data are described in Supporting Information.…”

European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia

“…Some of these may not be biologically driven and instead relate to non-adherence to therapy, which may be caused by a variety of reasons [ 154 ]. Others acquire diverse secondary abnormalities, including secondary ACAs and known or novel fusion genes [ 66 , 67 , 155 ] but none of these are clinically targetable and thus no specific investigations are considered as mandatory. As noted above, however, a myeloid gene panel may occasionally identify potentially targetable abnormalities in cases with overt relapse and evidence of disease progression.…”