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<p>Erythroid differentiation confers BCL-XL dependence and venetoclax resistance in acute myeloid leukemia (AML). However, whether myelodysplastic neoplasms (MDS) with erythroid predominance (EP), defined by ≥50% erythroid bone marrow elements, have distinct biology and drug sensitivities remains unknown. To study this, we evaluated an MDS patient cohort (<i>n</i> = 371) and showed that EP MDS (<i>n</i> = 67, 18%) are characterized by higher <i>TP53</i> (multihit <i>TP53</i>: 36% vs 17%, <i>p</i> = 0.004), <i>BCOR</i> and <i>WT1</i> and lower <i>ASXL1</i> and <i>SRSF2</i> mutation frequencies compared to non-EP (NEP) MDS (<i>n</i> = 304, 82%). <i>TP53</i>-mutant variant allele frequencies and allelic states correlated with erythroid population expansions. EP MDS was characterized by 3 genetic subgroups with distinct survival (<i>TP53</i> mutant: 11.4 months; splicing mutant: not reached; not otherwise specifiable (NOS): 19.5 months, <i>p</i> &lt; 0.001). EP MDS had a higher incidence of leukemic transformation (32% vs 12%, <i>p</i> = 0.040) and worse survival (8.3 months vs not reached, <i>p</i> = 0.041) after HMA-venetoclax therapy among 112 HMA-venetoclax-treated MDS patients. Expansion of erythroid populations during venetoclax failure was observed in 11 (33%) patients. EP MDS had higher BCL-XL expression levels at the RNA and protein levels compared to NEP MDS. These data support the dynamic assessment of erythroid predominance in MDS and warrant evaluation of BCL-XL inhibitors in these patients.</p>

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Erythroid-predominant myelodysplastic neoplasms exhibit a distinct genomic landscape with poor outcomes after venetoclax-based therapy

  • 期刊论文

  • 发表日期：

    2025年7月21日

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  • Alexandre Bazinet,
  • Sanam Loghavi,
  • Yue Wei,
  • Alex Bataller,
  • Koji Sasaki,
  • Naszrin Arani,
  • Faezeh Darbaniyan,
  • Kelly Chien,
  • Danielle Hammond,
  • Ian Bouligny,
  • Rashmi Kanagal-Shamanna,
  • Natthakan Thongon,
  • Guilin Tang,
  • Samuel Urrutia,
  • Tapan Kadia,
  • Courtney DiNardo,
  • Naval Daver,
  • Nicholas Short,
  • Ghayas Issa,
  • Naveen Pemmaraju,
  • Elias Jabbour,
  • Sa A. Wang,
  • Wei Wang,
  • Gautam Borthakur,
  • Carlos Bueso-Ramos,
  • Farhad Ravandi,
  • L. Jeffrey Medeiros,
  • Hagop Kantarjian,
  • Guillermo Garcia-Manero,
  • Guillermo Montalban-Bravo

摘要

Erythroid differentiation confers BCL-XL dependence and venetoclax resistance in acute myeloid leukemia (AML). However, whether myelodysplastic neoplasms (MDS) with erythroid predominance (EP), defined by ≥50% erythroid bone marrow elements, have distinct biology and drug sensitivities remains unknown. To study this, we evaluated an MDS patient cohort (n = 371) and showed that EP MDS (n = 67, 18%) are characterized by higher TP53 (multihit TP53: 36% vs 17%, p = 0.004), BCOR and WT1 and lower ASXL1 and SRSF2 mutation frequencies compared to non-EP (NEP) MDS (n = 304, 82%). TP53-mutant variant allele frequencies and allelic states correlated with erythroid population expansions. EP MDS was characterized by 3 genetic subgroups with distinct survival (TP53 mutant: 11.4 months; splicing mutant: not reached; not otherwise specifiable (NOS): 19.5 months, p < 0.001). EP MDS had a higher incidence of leukemic transformation (32% vs 12%, p = 0.040) and worse survival (8.3 months vs not reached, p = 0.041) after HMA-venetoclax therapy among 112 HMA-venetoclax-treated MDS patients. Expansion of erythroid populations during venetoclax failure was observed in 11 (33%) patients. EP MDS had higher BCL-XL expression levels at the RNA and protein levels compared to NEP MDS. These data support the dynamic assessment of erythroid predominance in MDS and warrant evaluation of BCL-XL inhibitors in these patients.