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Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.
Although the outcome of patients with acute myeloid leukemia (AML) has
improved in the past decades, the overall survival is below 50% [1, 2] and there
is still an unmet need for the development of new therapeutic strategies. Here,
we aimed to identify functional vulnerabilities in AML and investigated the
therapeutic potential of target structures involved in proteostasis, cell polarity and
RNA-binding molecular pathways.
We determined that genetic deletion of the cell fate determinant and polarity
regulator Scribble delays AML development, however, its deletion also seems to
affect the proliferative capacity of normal hematopoietic cells, lowering its value
as a therapeutic target. In contrast, inactivation of YBX1 (a pleiotropic protein with
DNA/RNA binding capacity that excerpts post-transcriptional control on its
targets) and PSMB8/LMP7 (a catalytic subunit of the immunoproteasome multiprotein
complex that belongs to the ubiquitin-proteasome system (UPS)) inhibit
leukemic cells without influencing normal hematopoietic stem and progenitor cell
function, establishing these targets as potential novel therapeutic strategies
against AML.
Genetic deletion of YBX1 caused reduced proliferation and colony forming
capacity in leukemic cells independent of the oncogenic driver mutation and
delayed AML development in vivo. The role of Ybx1 in leukemia maintenance
was investigated using a conditional knockout model, confirming the functional
requirement of Ybx1 in AML maintenance. Mechanistically, YBX1 recruited
oncogenic transcripts to polysomes, increasing their translation. Displacement of
these transcripts from polysomes after YBX1 deletion decreased their protein
expression.
Genetic and pharmacologic inhibition of PSMB8/LMP7 decreased proliferation
and colony forming capacity selectively in KMT2A (MLL)-rearranged leukemic
cells. In vivo treatment with a PSMB8/LMP7 inhibitor delayed disease
development in KMT2A-rearranged leukemic mice or patient derived xenografts
(PDX). We identified the transcriptional corepressor BASP1 as a functional
effector of the immunoproteasome. BASP1 was enriched after PSMB8/LMP7
inhibition and it was found binding to KMT2A-target genes. Moreover,
pharmacologic inhibition of PSMB8/LMP7 led to decreased expression of bonafide
KMT2A-fusion target genes and enrichment for genes deregulated by
inhibitors of the KMT2A complex partners DOT1L and MEN1. This prompted us
to investigate a potential synergism between MEN1 inhibition and
immunoproteasome inhibition. Combination treatment in AML cells revealed
decreased proliferation in vitro and increased survival in vivo as compared to the
single treatments, demonstrating the therapeutic potential of combining
immunoproteasome and MEN1 inhibitors.