Loss of the Non-Canonical BAF Complex as a Driver and Therapeutic Target in SF3B1-Mutant MDS and Leukemia


IN PARTNERSHIP WITH LEUKEMIA & LYMPHOMA SOCIETY AND THE PAUL G. ALLEN FRONTIERS GROUP (2020-PRESENT)

Robert Bradley, PhD, Fred Hutchinson Cancer Research Center

Before RNA transcribed from DNA leaves the nucleus to be translated into protein, it is processed or spliced to remove introns, nucleic acid segments that do not encode protein sequences. This requires the spliceosome, a large complex that correctly cuts and pastes together exons, the remaining genetic segments, leaving a mature messenger RNA molecule. When this process goes awry, large-scale dysregulation of genes can occur, sometimes resulting in uncontrolled cell proliferation. SF3B1, a component of the spliceosome, is commonly mutated in myelodysplastic syndrome (MDS) and leukemias, but its functional significance in these diseases is unclear.

Recently, it was discovered that SF3B1 mutations cause mis-splicing of a gene called BRD9 (part of the larger ncBAF complex) in samples taken from patients with MDS and leukemia. Loss of BRD9 in SF3B1-mutant cells causes them to grow more quickly and aggressively. In this project, Robert Bradley and his team are examining the functional consequences of BRD9 loss using a combination of splicing analysis and high throughput sequencing to identify factors that contribute to the aggressive phenotype. They are also testing two different therapeutic modalities that inhibit the function of mutant SF3B1 — antisense RNA oligonucleotides and small molecules. This work will validate the therapeutic potential of correcting mis-splicing events for treatment of blood cancers.

PUBLISHED RESEARCH

Takao S, Forbes L, Uni M, Cheng S, Pineda JMB, Tarumoto Y, Cifani P, Minuesa G, Chen C, Kharas MG, Bradley RK, Vakoc CR, Koche RP, Kentsis A. Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia. Elife. 2021.

Inoue D, Polaski JT, Taylor J, Castel P, Chen S, Kobayashi S, Hogg SJ, Hayashi Y, Pineda JMB, El Marabti E, Erickson C, Knorr K, Fukumoto M, Yamazaki H, Tanaka A, Fukui C, Lu SX, Durham BH, Liu B, Wang E, Mehta S, Zakheim D, Garippa R, Penson A, Chew GL, McCormick F, Bradley RK, Abdel-Wahab O. Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition. Nat Genet. 2021.

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