Molecule Information

General Information of the Molecule (ID: Mol04424)

• Name: Kelch-like protein 6 (KLHL6) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: KLHL6
• Gene ID: 89857
• Sequence:
  MLMAGQRGAWTMGDVVEKSLEGPLAPSTDEPSQKTGDLVEILNGEKVKFDDAGLSLILQN
  GLETLRMENALTDVILCVDIQEFSCHRVVLAAASNYFRAMFCNDLKEKYEKRIIIKGVD
  A ETMHTLLDYTYTSKALITKQNVQRVLEAANLFQFLRMVDACASFLTEALNPENCVGIL
  RL ADTHSLDSLKKQVQSYIIQNFVQILNSEEFLDLPVDTLHHILKSDDLYVTEEAQVFE
  TVM SWVRHKPSERLCLLPYVLENVRLPLLDPWYFVETVEADPLIRQCPEVFPLLQEARM
  YHLS GNEIISERTKPRMHEFQSEVFMIIGGCTKDERFVAEVTCLDPLRRSRLEVAKLPL
  TEHEL ESENKKWVEFACVTLKNEVYISGGKETQHDVWKYNSSINKWIQIEYLNIGRWRH
  KMVVLG GKVYVIGGFDGLQRINNVETYDPFHNCWSEAAPLLVHVSSFAATSHKKKLYVI
  GGGPNGK LATDKTQCYDPSTNKWSLKAAMPVEAKCINAVSFRDRIYVVGGAMRALYAYS
  PLEDSWCL VTQLSHERASCGIAPCNNRLYITGGRDEKNEVIATVLCWDPEAQKLTEECV
  LPRGVSHHG SVTIRKSYTHIRRIVPGAVSV
• Function: Involved in B-lymphocyte antigen receptor signaling andgerminal center formation. {ECO:0000250}.
• Uniprot ID: KLHL6_HUMAN
• Ensembl ID: ENSG0000017257812
• HGNC ID: HGNC:18653

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Preclinical Drug(s) 1 drug(s) in total

Nirogacestat-Ipatasertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [1]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Sensitive Drug: Nirogacestat-Ipatasertib
• Molecule Alteration: Missense mutation; Loss
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Notch signaling pathway; Inhibition; hsa04330
• In Vitro Model: U-2932 cells; Blood; Homo sapiens (Human); CVCL_1896
• In Vitro Model: TMD8 cells; Lymphoid; Homo sapiens (Human); CVCL_A442
• In Vitro Model: HLY-1 cells; Lymph; Homo sapiens (Human); CVCL_H207
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: OCI-Ly1 cells; Bone marrow; Homo sapiens (Human); CVCL_1879
• In Vitro Model: OCI-Ly7 cells; N.A.; Homo sapiens (Human); CVCL_1881
• In Vitro Model: Val cells; Bone marrow; Homo sapiens (Human); CVCL_1819
• In Vivo Model: NSG mice model; Mus musculus
• Experiment for Molecule Alteration: Immunoprecipitation assay; Biotin AP assay; Immunoblotting assay
• Experiment for Drug Resistance: CRISPR screen assay; MS assay; Flow cytometry assay; Drug sensitivity assay; RNA sequencing assay; Chromatin immunoprecipitation followed by sequencing assay
• Mechanism Description: DLBCL-associated NOTCH2 mutations evade ubiquitin-dependent degradation via the E3 ligases KLHL6 and FBXW7 and promote chemoresistance.Inhibition of gamma-secretase and AKT with nirogacestat and ipatasertib synergistically promotes CHOP-resistant DLBCL destruction.

References

• Ref 1: DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance. Blood. 2023 Sep 14;142(11):973-988.