Rotation Projects

The current research focuses on the role of non-coding RNAs (microRNAs, small nuclear RNAs, etc.) and mRNA splicing in cancer pathogenesis and therapeutic resistance, with strong emphasis on chemo- and immunotherapy

Aberrant splicing in cancer

 

1. To investigate the effects of aberrant splicing of cell surface antigens on cancer immunotherapy (CAR T cells, antibody-drug conjugates, etc)
Suggested reading:

Ang Z, Paruzzo L, Hayer KE, Schmidt C, Torres Diz M, Xu F, Zankharia U, Zhang Y, Soldan S, Zheng S, Falkenstein CD, Loftus JP, Yang SY, Asnani M, King Sainos P, Pillai V, Chong E, Li MM, Tasian SK, Barash Y, Lieberman PM, Ruella M, Schuster SJ, Thomas-Tikhonenko A. Alternative splicing of its 5'-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies. Blood. 2023 Nov 16;142(20):1724-1739. doi: 10.1182/blood.2023020400

Cortés-López M, Schulz L, Enculescu M, Paret C, Spiekermann B, Quesnel-Vallières M, Torres-Diz M, Unic S, Busch A, Orekhova A, Kuban M, Mesitov M, Mulorz MM, Shraim R, Kielisch F, Faber J, Barash Y, Thomas-Tikhonenko A, Zarnack K, Legewie S, König J. High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance. Nat Commun. 2022 Sep 22;13(1):5570. doi: 10.1038/s41467-022-31818-y

Cai T, Gouble A, Black KL, Skwarska A, Naqvi AS, Taylor D, Zhao M, Yuan Q, Sugita M, Zhang Q, Galetto R, Filipe S, Cavazos A, Han L, Kuruvilla V, Ma H, Weng C, Liu CG, Liu X, Konoplev S, Gu J, Tang G, Su X, Al-Atrash G, Ciurea S, Neelapu SS, Lane AA, Kantarjian H, Guzman ML, Pemmaraju N, Smith J, Thomas-Tikhonenko A, Konopleva M. Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells. Nat Commun. 2022 Apr 28;13(1):2228. doi: 10.1038/s41467-022-29669-8

Zheng S, Gillespie E, Naqvi AS, Hayer KE, Ang Z, Torres-Diz M, Quesnel-Vallières M, Hottman DA, Bagashev A, Chukinas J, Schmidt C, Asnani M, Shraim R, Taylor DM, Rheingold SR, O'Brien MM, Singh N, Lynch KW, Ruella M, Barash Y, Tasian SK, Thomas-Tikhonenko A. Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies. Blood Cancer Discov. 2022 Mar 1;3(2):103-115. doi: 10.1158/2643-3230.BCD-21-0087

Asnani M, Hayer, KE, Naqvi AS, Zheng S, Yang SY, Oldridge D, Ibrahim F, Maragkakis M, Gazzara MR, Black KL, Bagashev A, Taylor D, Mourelatos Z, Grupp SA, Barrett D, Maris JM, Sotillo E, Barash Y, Thomas-Tikhonenko, A. Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19. Leukemia 2020, 34(4):1202–1207.

Bagashev A, Sotillo E, Tang CA, Black KL, Perazzelli J, Seeholzer SH, Argon Y, Barrett DM, Grupp SA, Hu CA, Thomas-Tikhonenko A. CD19 alterations emerging after CD19-directed immunotherapy cause retention of the misfolded protein in the endoplasmic reticulum. Mol Cell Biol. 2018 Nov; 38(21): e00383-18, PMCID: PMC6189457

Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, Sussman R, Lanauze C, Ruella M, Gazzara MR, Martinez NM, Harrington CT, Chung EY, Perazzelli J, Hofmann TJ, Maude SL, Raman P, Barrera A, Gill S, Lacey SF, Melenhorst JJ, Allman D, Jacoby E, Fry T, Mackall C, Barash Y, Lynch KW, Maris JM, Grupp SA, Thomas-Tikhonenko A. Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov. 2015 Dec;5(12):1282-95.

 

2. To elucidate post-transcriptional mechanisms of cancer chemoresistance (aberrant splicing, protein degradation, etc.)

Suggested reading:

Torres-Diz M, Reglero C, Falkenstein CD, Castro A, Hayer KE, Radens CM, Quesnel-Vallières M, Ang Z, Sehgal P, Li MM, Barash Y, Tasian SK, Ferrando A, Thomas-Tikhonenko A. An Alternatively Spliced Gain-of-Function NT5C2 Isoform Contributes to Chemoresistance in Acute Lymphoblastic Leukemia. Cancer Res. 2024 Aug 2;. doi: 10.1158/0008-5472.CAN-23-3804

Yang SY, Hayer KE, Fazelinia H, Spruce LA, Asnani M, Black KL, Naqvi AS, Pillai V, Barash Y, Elenitoba-Johnson KSJ, Thomas-Tikhonenko A. FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells. Blood Adv. 2022 Nov 2;. doi: 10.1182/bloodadvances.2022007910

Harrington CT, Sotillo E, Dang CV, Thomas-Tikhonenko A. Tilting MYC toward cancer cell death. Trends Cancer. 2021 Nov;7(11):982-994

Harrington CT, Sotillo E, Robert A, Hayer KE, Bogusz AM, Psathas J, Yu D, Taylor D, Dang CV, Klein P, Hogarty MD, Geoerger B, El-Deiry WS, Wiels J, Thomas-Tikhonenko A. Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma. Leukemia. 2019 Oct 33(10): 2429–2441

 

3. To identify determinants of aberrant splicing in cancer, with focus on genetic variants and RNA-binding proteins

Suggested reading:

Quesnel-Vallières M, Jewell S, Lynch KW, Thomas-Tikhonenko A, Barash Y. MAJIQlopedia: an encyclopedia of RNA splicing variations in human tissues and cancer. Nucleic Acids Res. 2024 Jan 5;52(D1):D213-D221. doi: 10.1093/nar/gkad1043

Jha A, Quesnel-Vallières M, Wang D, Thomas-Tikhonenko A, Lynch KW, Barash Y. Identifying common transcriptome signatures of cancer by interpreting deep learning models. Genome Biol. 2022 May 17;23(1):117

Choi PS, Thomas-Tikhonenko A. RNA-binding proteins of COSMIC importance in cancer. J Clin Invest. 2021 Sep 15;131(18)

Slaff B, Radens CM, Jewell P, Jha A, Lahens NF, Grant GR, Thomas-Tikhonenko A, Lynch KW, Barash Y. MOCCASIN: a method for correcting for known and unknown confounders in RNA splicing analysis. Nat Commun. 2021 Jun 7;12(1):3353

Schulz L, Torres-Diz M, Cortés-López M, Hayer KE, Asnani M, Tasian SK, Barash Y, Sotillo E, Zarnack K, König J, Thomas-Tikhonenko A. Direct long-read RNA sequencing identifies a subset of questionable exitrons likely arising from reverse transcription artifacts. Genome Biol. 22(1):190, 2021

Black KL, Naqvi AS, Hayer KE, Yang SY, Gillespie E, Bagashev A, Pillai V, Tasian SK, Gazzara MR, Carroll M, Taylor D, Lynch KW, Barash Y, Thomas-Tikhonenko A. Aberrant splicing in B-cell acute lymphoblastic leukemia. Nucleic Acids Res 2018, 46(21):11357–11369