Alberti Lab

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We are a diverse and inclusive group of scientists cooperatively working to understand the role of mutant splicing factors in myeloid blood cancers in order to identify molecular vulnerabilities to therapeutically exploit and improve patient’s lives.

Our Research:

Large-scale DNA sequencing efforts from the past decade have successfully identified genes that are recurrently mutated in clonal myeloid malignancies (myelodysplastic syndromes [MDS], myeloproliferative neoplasms [MPN], and acute myeloid leukemia [AML]) and age-related clonal hematopoiesis (CH). Notably, these genes cluster into specific functional pathways, such as mRNA splicing, chromatin modification (e.g., ASXL1, BCOR, TET2), transcription, and signal transduction. The highly recurrent missense mutations in splicing factor (SF) genes (e.g., U2AF1, SRSF2, SF3B1) are usually associated with dysplastic morphologic features and found in >50% of patients with MDS or MDS/MPN and those who have developed secondary AML (sAML). SF mutations are typically identified in the founding clone of MDS patients, implicating dysregulation of RNA splicing as an important driver of disease. Although each of these SFs are integral to 3’-splice site recognition during splicing, each mutant leads to distinct aberrant splicing patterns in patients. Whether SF mutants converge on dysregulating a common molecular program through aberrant splicing or induce MDS through non-canonical mechanisms is still unknown. Most patients harbor additional genetic abnormalities, and the positive or negative enrichment of specific mutation pairs suggests cooperative or deleterious functional interactions between them. Most importantly, it is still fundamentally unclear how or why SF mutations gain clonal dominance in myeloid malignancies. Collectively, we hope to better understand the genetic and molecular basis of SF mutations in the initiation, development, and progression of CH and malignancy, and identify molecular liabilities to therapeutically target. In this regard, the lab is pursuing the following novel directions by employing a combination of novel genetically engineered mouse models and patient-derived samples in conjunction with high-throughput genomic approaches. Mutations in the U2AF1 gene provide an ideal model for these studies as they occur at one of two hotspot codons (S34 and Q157), and they are each associated with different clinical features, outcomes, alternative splicing, and co-occurring gene mutations in patients (Alberti et al, in preparation).

• Differential effects of mutant U2AF1-S34F and U2AF1-Q157R in hematopoietic diseases.
• Role of epigenetic dysregulation in SF mutant myeloid malignancies.
• Effects of aging and stress in selection of SF mutations in clonal hematopoiesis.

The Team:

• Michael O. Alberti, M.D., Ph.D. (Principal Investigator)
• Brittany LeBere (Lab Manager)
• Claire Ryan, M.Sc. (Research Professional)
• Thomas Salvetti (Research Professional)
• Bridget Hoag (CANB Graduate Student, Co-Mentored with Dr. James DeGregori [Primary])

The Alberti Lab is actively recruiting motivated and enthusiastic postdocs, graduate students, technicians, and part-time undergraduate students to work and assist on projects related to hematopoietic stem cells, alternative splicing, epigenetics, and blood cancer research! Please send a cover letter, CV (or resume), references, and research statements (for postdocs) to Dr. Alberti.

The lab also participates in the Cancer Research Experience for Undergraduates (CREU) and Gates Summer Internship Program (GSIP).

Lab Alumni:

• Ilana Baum (Gates Summer Internship Program, Summer 2023)
• Perpetual Kyei (CANB Graduate Program Rotation Student, Fall 2023)

Publications:

The Alberti Lab is committed to sharing our discoveries and contributions to blood cancer research with the scientific and lay communities in a timely and accessible manner. As such, we plan to support the following innovative publishing models as much as possible: bioRxiv, Review Commons, Life Science Alliance, and eLife. Full bibliography is available at MyNCBI. Selected references are below:

• U2AF1 is a haplo-essential gene required for hematopoietic cancer cell survival in mice. Wadugu B, Srivatsan SN, Heard A, Alberti MO, Ndonwi M, Liu J, Grieb S, Bradley J, Shao J, Ahmed T, Shirai CL, Khanna A, Fei DL, Miller CA, Graubert TA, Walter MJ. J Clin Invest. 2021 Nov 1;131(21):e141401. PMC8553566.
• Mutant U2AF1-induced alternative splicing of H2afy (macroH2A1) regulates B-lymphopoiesis in mice. Kim SP, Srivatsan SN, Chavez M, Shirai CL, White BS, Ahmed T, Alberti MO, Shao J, Nunley R, White LS, Bednarski J, Pehrson JR, Walter MJ. Cell Reports. 2021 Aug 31;36(9):109626. PMC8454217.
• Mutant TRP53-R172H has gain-of-function or dominant-negative effects in response to different hematopoietic stressors in mice. Ahmed T, Liu T, Alberti MO, Wadugu B, Ndonwi M, Grieb S, Walter MJ. Blood. 2020 Nov 5;136(Supplement 1):1. (Meeting abstract)
• Mutant U2AF1-S34F and U2AF1-Q157P induce distinct RNA splicing and hematopoietic phenotypes in vivo. Alberti MO, Zhu M, Srivatsan SN, Ahmed T, Shao JJ, Wadugu B, Shirai CL, Walter MJ. Blood. 2019 Nov 13;134(Supplement_1):770. (Meeting abstract)
• Discriminating a common somatic ASXL1 mutation (c.1934dup; p.G646Wfs*12) from artifact in myeloid malignancies using NGS. Alberti MO, Srivatsan SN, Shao J, McNulty SN, Chang GS, Miller CA, Dunlap JB, Yang F, Press RD, Gao Q, Ding L, Heusel JW, Duncavage EJ, Walter MJ. Leukemia. 2018 Aug;32(8):1874−1878. E-pub 2018 Jun 29. PMC6402595.

Current Funding:

• Lab Startup Package
  University of Colorado Anschutz Medical Campus Department of Pathology
  July 2022 – June 2026

   

• Distinct roles of U2AF1 mutations in myelodysplastic syndrome pathogenesis
  NHLBI K08 Career Development Award (K08 HL159354)
  July 2021 − June 2026

   

• Deconvoluting the molecular mechanisms of MDS pathogenesis by mutant U2AF1
  Edward P. Evans Foundation EvansMDS Young Investigator Award
  July 2021 – June 2024

• Targeting therapeutic vulnerabilities in myeloid pathogenesis
  CU Anschutz SOM Programmatic Incubator for Research (CU ASPIRE) Program Award
  July 2023 – June 2025
  

Lab Contact Info:

12801 E 17th Ave | RC-1 South, L18-5401K | Aurora, CO 80045 | United States

303-724-2934 | Twitter