Peripheral mononuclear cell samples obtained from 19 HL patients treated at our center with ICI (14 nivolumab only, 1 pembrolizumab only, and 4 both) were sequenced. Prior studies have demonstrated that KMT2C deletions enhance hematopoietic stem cell self-renewal and do give a fitness advantage in the presence of chemotherapy. None of the patients in our cohort has developed therapy-related MDS/AML though it could be a risk in the future.

2 years ago

Clinical • PARP Biomarker • PD(L)-1 Biomarker • IO biomarker

DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • KMT2C (Lysine Methyltransferase 2C) • NOTCH2 (Notch 2) • MSH3 (MutS Homolog 3) • MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1) • FCGR3A (Fc Fragment Of IgG Receptor IIIa) • CHD4 (Chromodomain Helicase DNA Binding Protein 4) • HNF1A (HNF1 Homeobox A)

KMT2C mutation • MLL3 deletion • MLL3 mutation

Keytruda (pembrolizumab) • Opdivo (nivolumab)

over3years

[VIRTUAL] GENOMIC ANALYSES IN T-ALL PATIENTS IDENTIFY RECURRENT AND NOVEL ABNORMALITIES (EHA 2021)

We identified several co-occurring lesions as well as mutually exclusive genomic abnormalities. Secondary PDX models investigating targeted treatment strategies are ongoing.

over 3 years ago

Clinical • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • NOTCH1 (Notch 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • IKZF1 (IKAROS Family Zinc Finger 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • WT1 (WT1 Transcription Factor) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor) • JAK3 (Janus Kinase 3) • NUP214 (Nucleoporin 214) • PHF6 (PHD Finger Protein 6) • TYK2 (Tyrosine Kinase 2) • LCK (LCK Proto-Oncogene, Src Family Tyrosine Kinase) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • DDX3X (DEAD-Box Helicase 3 X-Linked) • MLLT10 (MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor)

KRAS mutation • PTEN deletion • CDKN2A deletion • JAK3 mutation • MLL3 deletion

almost4years

Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy. (PubMed, Cell Rep)

Kmt2c deletions mitigate histone methylation/acetylation changes that accrue as HSCs cycle after chemotherapy, and they impair enhancer recruitment during HSC differentiation. These findings help explain why Kmt2c deletions are more common in t-MDS/t-AML than in de novo AML or clonal hematopoiesis: they selectively protect cycling HSCs from differentiation without inducing HSC proliferation themselves.

almost 4 years ago

Journal

KMT2C (Lysine Methyltransferase 2C)

KMT2C mutation • MLL3 deletion

4years

[VIRTUAL] Next Generation Genomic Analyses in T-ALL Patients Identify Recurrent and Novel Genomic Abnormalities (ASH 2020)

The top 20 mutated genes in our patient cohort differ to those reported for a pediatric cohort (Roberts et al 2019 Blood 134:649), indicating an association between patient age and genomic alteration. Secondary PDX models investigating novel targeted treatment strategies are ongoing.

4 years ago

Clinical • BRCA Biomarker • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • NOTCH1 (Notch 1) • JAK2 (Janus kinase 2) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • RUNX1 (RUNX Family Transcription Factor 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • IKZF1 (IKAROS Family Zinc Finger 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • NOTCH2 (Notch 2) • CHEK2 (Checkpoint kinase 2) • AFF1 (AF4/FMR2 Family Member 1) • IL7R (Interleukin 7 Receptor) • JAK3 (Janus Kinase 3) • NUP214 (Nucleoporin 214) • TYK2 (Tyrosine Kinase 2) • LCK (LCK Proto-Oncogene, Src Family Tyrosine Kinase) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • SMARCD1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily D, Member 1)

KRAS mutation • PTEN deletion • CDKN2A deletion • JAK3 mutation • NUP214-ABL1 fusion • ABL1 deletion • MLL3 deletion