Deletion of chr. 20q (del20q) is detected in 5-8% of myeloid neoplasms and is one of the most frequent age-related CHIP events, arising in 1 in 1,000 adults. Because del20q is a cytogenetic hallmark of both MDS and MPN, healthy carriers appear to have a higher propensity of progression to MDS and MPN than carriers of other CHIP lesions. While isolated del20q is classified as a low-risk lesion in the IPSS-M criteria, it is re-classified to intermediate risk (when isolated) and high risk in AML when accompanied by another cytogenetic lesion per the 2022 ELN criteria. Despite its recognized clinical importance, there is limited understanding of the genetic etiology driving its leukemogenic effects, and targeted therapies do not exist.

In this study, we aimed to define the genetic regulatory framework by which del20q is proleukemic and to determine potential targeted therapies. We hypothesized that a proleukemogenic effect of del20q is due to haploinsufficiency (HI) of a tumor suppressor gene (TSG) or loss of heterozygosity (LOH) of a TSG due to a somatic or germline mutation.

Using matched tumor-normal NGS and SNP-array profiling on 2,766 diploid myeloid cases and 79 del20q cases, we found no recurrent germline or somatic LOH. Among pathogenic somatic variants, only U2AF1 was enriched in the del20q group (16% vs 7%). SNP-array mapping of 79 del20q samples revealed a common deleted region (CDR) at 20q11.22-q13.13 in >70% of patients, harboring 126 coding genes of which 94 were transcriptionally down-regulated and 68 showed copy-number–expression correlation, consistent with HI rather than a focal driver mutation. To interrogate the functional impact of the 20q11.22-q13.13 deletion, we next applied PANDA, an algorithm that integrates TF–binding-motif priors, gene-expression correlations and protein interactions to infer master regulators. Among these, none of the previously considered 20q candidate drivers emerged as central regulators, highlighting a previously unrecognized regulatory core within the CDR.

From this network, PHF20 surfaced as a dominant hub. PHF20, abundant in CD34⁺ myeloid precursors, functions as a TSG in glioblastoma and melanoma. It acetylates H4K16 (required for erythroid maturation), and TP53, protecting p53 from MDM2-driven degradation. Consistent with these roles, preliminary results in a PHF20 knockdown model in TF-1 cells showed accelerated proliferation and rendered the line cytokine-independent, functionally validating its leukemogenic potential. Transcriptome-wide analysis of del20q patient samples revealed an inverse correlation between PHF20 and HDAC2 expression (r²=0.40, p=0.047); HDAC2 is the chief de-acetylase that removes H4K16ac, and loss of PHF20 appears to shift chromatin toward a heterochromatic, differentiation-blocked state.

We screened six primary del20q AML samples and found marked BCL-2 dependence: venetoclax IC₅₀ 0.12 µM versus 0.48 µM in diploid controls (ΔAUC –0.23, p=0.009) and a similar differential for ABT-737 (ΔAUC –0.21, p=0.012). In two tested samples, panobinostat showed promising activity (ΔAUC +0.17, p=0.17), suggesting that the PHF20–HDAC2 axis is therapeutically exploitable. A broader screen of primary cells carrying del20q and other lesions is underway to refine these therapeutic leads.

Del20q explains only a subset of PHF20 deficiency; thereby, we screened 994 diploid AML cases (TCGA/BEAT-AML) and found 51 “PHF20-low” samples (mRNA z ≤ –1.5) that phenocopied the del20q expression profile. These patients were older (61 vs 57 y), favored FAB M1/M5 (24% vs 10%), had lower platelets (79 vs 109 × 10⁹/L), fewer blasts (11% vs 26%), and shorter survival (median 9.6 vs 12.2 mo). They also showed a 15% HDAC2 up-shift and double the TP53-mutation rate (18% vs 8%). Whether via deletion or repression, PHF20 haploinsufficiency funnels cells into an HDAC2-dominated, p53-sensitized state, nominating venetoclax, potentially combined with HDAC inhibition, as a rational therapeutic strategy for PHF20-low myeloid disease.

In summary, our integrative multi-omics analyses positions PHF20 as a key driver of del20q leukemogenesis, defines an actionable PHF20–HDAC2 regulatory circuit, and exposes a selective dependence on BCL-2 signaling. These insights identify venetoclax-based regimens, potentially potentiated by HDAC inhibition, as rational guided therapies for PHF20-low myeloid neoplasms. The functional effects using del20q are ongoing to assess the role of PHF20 in vitro.

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2025
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