SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities

Abstract

Hematological malignancies are a highly heterogeneous group of diseases with varied molecular and phenotypical characteristics. SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes play significant roles in the regulation of gene expression, being essential for processes such as cell maintenance and differentiation in hematopoietic stem cells. Furthermore, alterations in SWI/SNF complex subunits, especially in ARID1A/1B/2, SMARCA2/4, and BCL7A, are highly recurrent across a wide variety of lymphoid and myeloid malignancies. Most genetic alterations cause a loss of function of the subunit, suggesting a tumor suppressor role. However, SWI/SNF subunits can also be required for tumor maintenance or even play an oncogenic role in certain disease contexts. The recurrent alterations of SWI/SNF subunits highlight not only the biological relevance of SWI/SNF complexes in hematological malignancies but also their clinical potential. In particular, increasing evidence has shown that mutations in SWI/SNF complex subunits confer resistance to several antineoplastic agents routinely used for the treatment of hematological malignancies. Furthermore, mutations in SWI/SNF subunits often create synthetic lethality relationships with other SWI/SNF or non-SWI/SNF proteins that could be exploited therapeutically. In conclusion, SWI/SNF complexes are recurrently altered in hematological malignancies and some SWI/SNF subunits may be essential for tumor maintenance. These alterations, as well as their synthetic lethal relationships with SWI/SNF and non-SWI/SNF proteins, may be pharmacologically exploited for the treatment of diverse hematological cancers.

Keywords: BAF complexes; Chromatin remodeling; Drug resistance; Epigenetics; Leukemia; Lymphoma; Multiple myeloma; SWI/SNF; Synthetic lethality.

Fig. 1

Summary of the main genetic alterations in SWI/SNF subunits in hematological malignancies. Because alteration frequencies can vary greatly between cohorts of the same disease (Table 3), they have been roughly categorized in three discrete groups. Double arrows indicate paralogous subunits that can play equivalent roles in different complexes. ALAL: acute leukemia of ambiguous lineage; ALL: acute lymphoblastic leukemia; APL: acute promyelocytic leukemia; BL: Burkitt lymphoma; BPDCN: blastic plasmacytoid dendritic cell neoplasm; CLL: chronic lymphocytic leukemia; CML: chronic myeloid leukemia; CTCL: cutaneous T cell lymphoma; DLBCL: diffuse large B cell lymphoma; EATL: enteropathy-associated T cell lymphoma; ENKTL: extranodal NK/T cell lymphoma; FL: follicular lymphoma; HSTCL: hepatosplenic T cell lymphoma; LPL: Lymphoplasmacytic lymphoma; MCL: mantle cell lymphoma; MDS: myelodysplastic syndrome; MF: mycosis fungoides; MZL: marginal zone lymphoma; PLL: prolymphocytic leukemia; PMBL: primary mediastinal large B-cell lymphoma; PTCL: peripheral T cell lymphoma, not otherwise specified. *Limited study, see Table 3

Fig. 2

Mutations in SWI/SNF genes in diffuse large B cell lymphoma (DLBCL). A Proportion of DLBCLs that have at least one mutation (mut.) in one SWI/SNF gene in whole-exome sequencing (WES) or whole-genome sequencing (WGS) studies. WT: wild type. Data sources: [7, 8, 82, 83]. In the datasets of Reddy et al. and Schmitz et al., previously missed splice site mutations from our previous reports have been added [86, 115]. B Distribution of mutations in BCL7A, shown at the protein level. Exon 1 (amino acids 1-31) is highlighted in red. Data sources: [–9, 82, 83, 108]. C Distribution of mutations in SWI/SNF genes in DLBCL in WES or WGS studies. Data sources: [7, 8, 82, 83]. For the cohort of Chapuy et al., only paired samples were included in the plot. ABC: activated B cell-like; GCB: germinal center B cell-like

Fig. 3

Therapeutic opportunities and resistances generated by altered SWI/SNF complexes in hematological malignancies. Altered subunits (depicted in red) create dependencies on other subunits or pathways/activities that can be exploited (blunt red arrows). Aberrant SWI/SNF complexes confer resistance to routinely used antineoplastic drugs (black arrows). The rest of the subunits of the SWI/SNF complex are shown in grey. ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; CML: chronic myeloid leukemia; MCL: mantle cell lymphoma; MM: multiple myeloma; NHL: non-Hodgkin lymphoma; PRC2: polycomb repressive complex 2