Fusion Gene KMT2A::SEPTIN6 in Acute Myeloid Leukemia Cell Line KOPM-88

Area of Science:

• Hematology
• Molecular Biology
• Genetics

Background:

• KMT2A (MLL) gene alterations, including fusions and partial tandem duplications (PTD), are implicated in acute leukemias.
• Over 100 KMT2A fusion genes exist, but few are represented by cell line models.
• Understanding KMT2A rearrangements is crucial for targeted acute myeloid leukemia (AML) therapies.

Purpose of the Study:

• To characterize the genetic aberrations in the acute myeloid leukemia (AML) cell line KOPM-88.
• To identify and functionally analyze novel KMT2A rearrangements in AML.
• To establish a cell line model for studying KMT2A::SEPTIN6 fusion in AML.

Main Methods:

• Cytogenetic and genomic analyses (copy number, PCR, Western blot, RNA-sequencing) of KOPM-88 cell line.
• Bioinformatic analysis of public AML patient data for differentially expressed genes.
• Functional assays including siRNA-mediated knockdown and live-cell imaging.

Main Results:

• KOPM-88 harbors the KMT2A::SEPTIN6 fusion gene, resulting from a t(X;11)(q24;q23) translocation, excluding KMT2A-PTD.
• The KMT2A::SEPTIN6 fusion activates bone morphogenetic protein (BMP) signaling.
• BMP signaling upregulates cell proliferation and downregulates CDKN2B expression, while inhibiting HOXA7 and HOXA9.

Conclusions:

• KOPM-88 is the sole cell line model for the rare KMT2A::SEPTIN6 fusion.
• This cell line provides a valuable tool for investigating KMT2A::SEPTIN6-positive AML.
• KOPM-88 may facilitate the development of novel therapeutic strategies for this specific AML subtype.