Many of us misunderstand KMT2A leukemia. FDA says “translocation”—biology says fusion. FISH ≠ partner. DNA panels miss it. Only KMT2Ar responds. Break-apart tells you that. RNA tells you what. Biology tells you if it matters.

TP53 in MDS is not binary. It’s a spectrum. And we’re oversimplifying it ! Large SCT dataset confirms: • TP53-mut = adverse • “Biallelic” = worst Important work. But the biology is more nuanced. Monoallelic TP53? Bad. But how bad? We all have long-term SCT survivors → 👉 suggests residual function / heterogeneity True biallelic (multi-hit)? • Functional TP53 loss • Genomic instability • Near chemo-resistant state 👉 Very difficult to rescue, even with SCT But here’s the issue: “Biallelic” often defined as VAF >50% 👉 Useful shortcut 👉 Not biology VAF >50% ≠ biallelic VAF reflects: • Tumor purity • Clonal dominance • Copy number A dominant monoallelic clone can look like “50%” More importantly: 👉 What if TP53 is a 10% subclone? Different biology: • Less genomic dominance • Less clonal fitness 👉 GVL may still control this So TP53-mut disease is not one entity: • Monoallelic dominant • True multi-hit • Small subclonal TP53 ➡️ Different biology ➡️ Different outcomes Retrospective studies like this are critical —but limited by simplified definitions TP53 is a spectrum VAF is not allelic state True biallelic = genomic collapse Subclonal TP53 → may be GVL-sensitive See figure 👇 Dr Fun + G #MDS #AML #Hemetwitter

Thank you. MYC rearranged ≠ Burkitt WHO5 / ICC: • Burkitt → MYC-R + classic biology • DH/TH → MYC + BCL2/BCL6 • HGBL-NOS → MYC-R, no partner • DLBCL can still be MYC+ Clinical truth: MYC = high-grade behavior signal