"Double-hit"RUNX1 Involving a Novel t(6;21)(q25;q22) Chromosome Translocation with RUNX1::ARID1B Gene Rearrangement and RUNX1 p.Trp279* truncation in Acute Myeloid Leukemia
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction:
The RUNX1 gene encodes a core binding factor subunit that regulates hematopoiesis, contributing to differentiation into myeloid and lymphoid cells. Around 70 RUNX1 translocations are known, with t(8;21)(q22;q22) being the most common in de novo acute myeloid leukemia (AML). This study reports an AML case with pathogenic variants in RUNX1 and IDH1, along with a novel (6;21)(q25;q22) translocation, leading to a "double hit" RUNX1.
Methods:
The Patient is an 81-year-old female with a diagnosis of AML. At diagnosis, her bone marrow aspirate showed a myeloid leukemia infiltrate. Flow cytometry identified 43% myeloblasts. Initial cytogenetic studies revealed a normal karyotype with normal fluorescent in situ hybridization (FISH) studies. By Next generation sequencing (NGS), one pathogenic and one likely pathogenic variant were detected at diagnosis: IDH1 p.Arg132Gly and RUNX1 p.Trp279*. The patient underwent treatment with Venetoclax and Azacitidine (VEN-AZA) therapy. After 2 months, patient showed normocellular hematopoiesis and flowcytometry, cytogenetics and FISH were negative for evident residual disease; however, the IDH1 pathogenic sequence variant was detected by PCR. She continued therapy with VEN-AZA. The bone marrow study after 6 cycles showed complete remission and the IDH1 sequence variant was undetectable at this time. The patient was then lost to follow up for 17 months. On subsequent follow up, the bone marrow showed 43% blasts with 38.7% circulating blasts. Cytogenetic analysis of the bone marrow sample at this time showed a complex karyotype: 45,XX,der(9;17)(17qter->17p13::17q11.2->17q25::?::9p24->9qter),t(11;13)(p13;q12),add(14)(q11.2),-17,del(21)(q22q22),+mar[20]. Hybridization to abnormal cells with the RUNX1 probe revealed an additional RUNX1 signal on the long (q) arm of chromosome 6, suggesting a cryptic (6;21) translocation. NGS identified additional molecular abnormalities beyond the previously detected IDH1 and RUNX1 mutations, including ASXL1, DNMT3A, and BAX. A RNAseq analysis revealed a RUNX1::ARID1B gene fusion, consistent with the cytogenetic findings of a cryptic (6;21) translocation. In addition, copy number variants detected included hemizygous deletion in JAK2, WTI, NF1, and U2AF1. The patient received treatment with Azacitidine and Ivosedinib but passed away seven months later.
Results:
Consistent with the literature, alterations in ASXL1, DNMT3A, U2AF1, and WTI were identified, highlighting their role in clonal evolution and disease progression in AML. ARID1B, a component of the chromatin remodeling complex, may contribute to transcriptional dysregulation and cell cycle activation.
Conclusion:
Further molecular studies, including single-cell analysis, are essential to deepen our understanding of disease progression, relapse, and new treatment strategies in these patients.
The RUNX1 gene encodes a core binding factor subunit that regulates hematopoiesis, contributing to differentiation into myeloid and lymphoid cells. Around 70 RUNX1 translocations are known, with t(8;21)(q22;q22) being the most common in de novo acute myeloid leukemia (AML). This study reports an AML case with pathogenic variants in RUNX1 and IDH1, along with a novel (6;21)(q25;q22) translocation, leading to a "double hit" RUNX1.
Methods:
The Patient is an 81-year-old female with a diagnosis of AML. At diagnosis, her bone marrow aspirate showed a myeloid leukemia infiltrate. Flow cytometry identified 43% myeloblasts. Initial cytogenetic studies revealed a normal karyotype with normal fluorescent in situ hybridization (FISH) studies. By Next generation sequencing (NGS), one pathogenic and one likely pathogenic variant were detected at diagnosis: IDH1 p.Arg132Gly and RUNX1 p.Trp279*. The patient underwent treatment with Venetoclax and Azacitidine (VEN-AZA) therapy. After 2 months, patient showed normocellular hematopoiesis and flowcytometry, cytogenetics and FISH were negative for evident residual disease; however, the IDH1 pathogenic sequence variant was detected by PCR. She continued therapy with VEN-AZA. The bone marrow study after 6 cycles showed complete remission and the IDH1 sequence variant was undetectable at this time. The patient was then lost to follow up for 17 months. On subsequent follow up, the bone marrow showed 43% blasts with 38.7% circulating blasts. Cytogenetic analysis of the bone marrow sample at this time showed a complex karyotype: 45,XX,der(9;17)(17qter->17p13::17q11.2->17q25::?::9p24->9qter),t(11;13)(p13;q12),add(14)(q11.2),-17,del(21)(q22q22),+mar[20]. Hybridization to abnormal cells with the RUNX1 probe revealed an additional RUNX1 signal on the long (q) arm of chromosome 6, suggesting a cryptic (6;21) translocation. NGS identified additional molecular abnormalities beyond the previously detected IDH1 and RUNX1 mutations, including ASXL1, DNMT3A, and BAX. A RNAseq analysis revealed a RUNX1::ARID1B gene fusion, consistent with the cytogenetic findings of a cryptic (6;21) translocation. In addition, copy number variants detected included hemizygous deletion in JAK2, WTI, NF1, and U2AF1. The patient received treatment with Azacitidine and Ivosedinib but passed away seven months later.
Results:
Consistent with the literature, alterations in ASXL1, DNMT3A, U2AF1, and WTI were identified, highlighting their role in clonal evolution and disease progression in AML. ARID1B, a component of the chromatin remodeling complex, may contribute to transcriptional dysregulation and cell cycle activation.
Conclusion:
Further molecular studies, including single-cell analysis, are essential to deepen our understanding of disease progression, relapse, and new treatment strategies in these patients.