Molecular and Clinical Spectra of Protein Phosphatase, Mg2+/Mn2+-Dependent 1D (PPM1D)-Mutant Myeloid Neoplasms

Protein phosphatase Mg2+/Mn2+-dependent 1D (PPM1D) gene (17q23) cooperates with TP53 in regulating DNA damage response (DDR). PPM1D^MT are frequently encountered in clonal hematopoiesis of indeterminate potential (CHIP) and in therapy-related myeloid neoplasms (t-MN). Most typically lesions lead to C-terminal loss leading to truncation with paradoxical gain-of-function amplification of PPM1D effects in terms of inactivation of TP53 and are thus functionally synergistic with TP53 deficiency. Here, we investigated the clonal architecture and clinical implications of PPM1D^MT in the context of TP53^MT MN.

A cohort of 4479 patients (pts) screened for the presence of PPM1D^MT and TP53^MT was analyzed in terms of clinical phenotype, cytogenetics, clonal hierarchy and outcomes (see Table). Overall, 67 (1.5%) pts harbored PPM1D^MT and 367 (8%) TP53^MT. PPM1D^MT (n=70) were truncating, of which 57% were frameshift and 43% were stop codons, distributed across exon 6. No biallelic PPM1D^MT case was found. When we studied PPM1D expression in wild type, mRNA levels were elevated in AML (59%; P<.0001, but not in MDS), with high risk AML having higher expression PPM1D levels compared to favorable cases (59% vs. 46%, P=.08). PPM1D^MT cases were older than those with TP53^MT [median 74yrs (range, 39-93) vs. 71yrs (14-95), P=.02]. PPM1D^MT were significantly enriched within pts with CH (including CHIP and CCUS) compared to TP53^MT (27 vs. 1%, P=.0001) while TP53^MT were more frequently encountered in MN (71 vs. 31%, P=.0001). Review of the medical records of PPM1D^MT and TP53^MT cases revealed history of malignancy was ascertained in 69% of PPM1D^MTvs. 30% in TP53^MT; P<.0001, of which 30% had hematological malignancies (HM) and 7.5% were breast cancer (BC) survivors. Of note is that 9% PPMD1^MT cases had autoimmune disorders. Overall, 37% received only chemotherapy, 20% radiotherapy only, 22% both chemo/radiotherapy and 13% immunosuppression. A total of 14% of TP53^MT carriers had a prior history of HM and 5% had BC history. When compared to PPM1D^MT, a higher fraction (58%; P=.005) received chemotherapy, whereas similar rates were noted for radiotherapy (14%), chemo/radiotherapy combination (17%) and immunosuppression (11%).

PPM1D^MT were also more commonly found in t-MN than TP53^MT (42 vs. 28%, P=.05). Overall, 37% of PPM1D^MT showed a normal karyotype (NK) compared to 14% of TP53^MT (P=.0003). Indeed, up to 61% of TP53^MT had complex karyotypes (CK vs. 15% in PPM1D^MT, P=.0001). Most common genes associated with PPM1D^MTvs.TP53^MT were DNMT3A (21 vs. 10%; P=.05), TET2 (19 vs. 11%; P=.2), ASXL1 (15 vs. 10%, P=.4), KRAS/NRAS (1 vs 7%, P=.06) and NF1 (1 vs. 7%, P=.03).

Analysis of clonal architecture showed that PPM1D^MT were either dominant / codominant (46%; n=33) including PPM1D^MT as a sole lesion(n=19); in these cases TP53^MT was the most common 2^nd/codominant hit (25%) followed by DNMT3A (12.5%, P=.04) and RUNX1 (12.5%, P=.04). Cases with dominant PPM1D^MT were encountered more in t-MN (46 vs. 36%, P=.3) and CH (30 vs. 24%, P=.4) compared to subclonal PPM1D^MT (n=34, 51%), which were subclonal to TET2^MT (21%) followed by JAK2 (12%), DNMT3A (9%, P=.02) and TP53 (9%, P=.02). Notably, all deaths in PPM1D^MT CH cases were not due to progression to MN. No significant difference was found in OS between ancestral and subclonal PPM1D^MT carriers.

PPM1D^MT were more likely encountered in older pts (OR=3.2; P=.001), MN-LR (OR=2.8, P<.0001), CH (OR=12.6, P<.0001), t-MN (OR=4.8, P<.0001), NK (OR=1.9, P=.01) and DNMT3A^MT carriers (OR=1.86, P=.04) and less likely to occur in pts with MN-HR (OR=0.38, P=.002; see Figure)

Survival analysis showed no significant difference between PPM1D^MT and PPM1D^WT and between CH and non-CH PPM1D^MT cases while there was a significant difference between PPM1D^MTvs. TP53^MT (102 vs.12mo., P<.0001).Of note is that 12 pts had both PPM1D^MT and TP53^MT (50% t-MN, of which 25% had a prior history of lymphoma). In such cases, PPM1D^MT were mostly ancestral compared to TP53^MT (67 vs. 33%; P<.0001).

Configurations of PPM1D in the clonal hierarchy and pairing with secondary or primary hits are consistent with their role in MN evolving from CH. Association with CH implies that some of the t-MN may be derived from pre-existing CH a theory which we are currently being testing in serial samples.

Patel:Apellis Pharmaceuticals: Consultancy, Other: Teaching and Speaking; Novartis Pharmaceuticals: Consultancy; Alexion: Consultancy, Other: Teaching and Speaking. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion: Consultancy.