Mechanisms of Tumor-Initiation in B-Lymphoid Malignancies


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

Markus Müschen, MD, PhD, City of Hope

In cancers of the hematopoietic and lymphoid tissues, leukemia initiating cells (LICs), which give rise to the disease, are refractory to treatment and are often a major contributor to relapse and recurrence. Therefore, targeting LICs is an appealing strategy to treat these cancers. Markus Müschen and his team have uncovered that LGR5, a protein involved in the WNT/β-catenin pathway, is expressed in B cell lineage LICs (B-LIC) and is necessary for their viability. Interestingly, they found that LGR5 is an inhibitor of β-catenin signaling in B cells, which seem to be unique in their aversion to activating mutations in the WNT/β-catenin pathway, unlike most other cancers. Dr. Müschen and his team are examining how expression of LRG5 induces self-renewal in B-LIC, probing the function and prognostic and therapeutic usefulness of LRG5 as a marker in B-cell malignancies, and determining whether existing or novel treatments targeting this protein will promote long-lasting response in these cancers.

PUBLISHED RESEARCH

Lee J, Robinson ME, Ma N, Artadji D, Ahmed MA, Xiao G, Sadras T, Deb G, Winchester J, Cosgun KN, Geng H, Chan LN, Kume K, Miettinen TP, Zhang Y, Nix MA, Klemm L, Chen CW, Chen J, Khairnar V, Wiita AP, Thomas-Tikhonenko A, Farzan M, Jung JU, Weinstock DM, Manalis SR, Diamond MS, Vaidehi N, Müschen M. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. Nature. 2020.

Sadras T, Martin M, Kume K, Robinson ME, Saravanakumar S, Lenz G, Chen Z, Song JY, Siddiqi T, Oksa L, Knapp AM, Cutler J, Cosgun KN, Klemm L, Ecker V, Winchester J, Ghergus D, Soulas-Sprauel P, Kiefer F, Heisterkamp N, Pandey A, Ngo V, Wang L, Jumaa H, Buchner M, Ruland J, Chan WC, Meffre E, Martin T, Müschen M. Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer. Mol Cell. 2021.

Pan L, Hong C, Chan LN, Xiao G, Malvi P, Robinson ME, Geng H, Reddy ST, Lee J, Khairnar V, Cosgun KN, Xu L, Kume K, Sadras T, Wang S, Wajapeyee N, Müschen M. PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis. Proc Natl Acad Sci U S A. 2021.

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