Tefferi, A. | bioRxiv Science

bioRxiv2023

Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in [~]25% of patients ( chr21amp). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A, a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo, and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.

cancer biology↗

bioRxiv2020

Indoleamine 2,3-dioxygenase-1 expressing aggregate bone marrow dendritic cell populations are associated with systemic T cell compartment changes in chronic myelomonocytic leukemia

Systemic immune tolerance is not well-characterized in chronic myelomonocytic leukemia (CMML). Due to the presence of clonal plasmacytoid dendritic cells (pDC) in CMML, and the established association of lymph node indoleamine 2,3-dioxygenase-1 (IDO1)-positive (+) DC populations (IDC) with systemic immune tolerance in other malignant contexts, we sought to determine the association of IDO1 expression and bone marrow (BM) DC populations with systemic T-cell compartment changes using primary CMML patient samples (BM, plasma, and peripheral blood mononuclear cells) via immunohistochemistry (IHC), liquid chromatography-mass spectrometry (LC-MS), and time-of-flight mass cytometry (CyTOF). Our results highlight that aggregate BM IDC (CD123 and/or CD11c positive) occur in 33% CMML patients at any disease time-point (IHC), correlate with accentuated tryptophan catabolism (LC-MS, increased kynurenine level, median 4.7 versus 3 microM, P=0.049*), systemic regulatory T-cell expansion (CyTOF, %parent cell type, 14.5 versus 4.9%, P=0.04*) and play a role in disease progression, as evidenced by a higher rate of transformation to acute myeloid leukemia (41 versus 13%, P=0.002**), when compared to CMML patients without BM IDC. Our data also highlight a perturbed immune system in CMML with specific systemic immune signatures, particularly type 1, IL-17 producing helper T, CD4 terminal effector and natural killer cell suppression. Key PointsO_LIAggregate IDO1+ dendritic cell populations occur in the CMML bone marrow microenvironment, and their presence correlates with disease progression. C_LIO_LISystemic immune microenvironment signatures in CMML indicate an altered T- and natural killer (NK)-cell balance. Specifically, suppression of type 1 helper T (Th1), IL-17 producing helper T (Th17), CD4 terminal effector and NK cells. C_LIO_LIIDO1+ bone marrow dendritic cell populations in CMML are associated with a T-cell compartment shift towards a regulatory T cell phenotype. C_LI

immunology↗