Mutant Ikzf1, KrasG12D, and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents.
Mice that accurately model the genetic diversity found in human cancer are valuable tools for interrogating disease mechanisms and investigating novel therapeutic strategies. We performed insertional mutagenesis with the MOL4070LTR retrovirus in Mx1-Cre, Kras(G12D) mice and generated a large cohort of T lineage acute lymphoblastic leukemias (T-ALLs). Molecular analysis infers that retroviral integration within Ikzf1 is an early event in leukemogenesis that precedes Kras(G12D) expression and later acquisition of somatic Notch1 mutations. Importantly, biochemical analysis uncovered unexpected heterogeneity, which suggests that Ras signaling networks are remodeled during multistep tumorigenesis. We tested tumor-derived cell lines to identify biomarkers of therapeutic response to targeted inhibitors. Whereas all T-ALLs tested were sensitive to a dual-specificity phosphoinosityl 3-kinase/mammalian target of rapamycin inhibitor, biochemical evidence of Notch1 activation correlated with sensitivity to gamma-secretase inhibition. In addition, Kras(G12D) T-ALLs were more responsive to a MAP/ERK kinase inhibitor in vitro and in vivo. Together, these studies identify a genetic pathway involving Ikzf1, Kras(G12D), and Notch1 in T lineage leukemogenesis, reveal unexpected diversity in Ras-regulated signaling networks, and define biomarkers of drug responses that may inform treatment strategies.
Dail
Monique
M
Departments of Pediatrics, Medicine, Laboratory Medicine, and Pharmaceutical Chemistry, University of California, San Francisco, CA 94143, USA.
Li
Qing
Q
McDaniel
Andrew
A
Wong
Jason
J
Akagi
Keiko
K
Huang
Ben
B
Kang
Hio Chung
HC
Kogan
Scott C
SC
Shokat
Kevan
K
Wolff
Linda
L
Braun
Benjamin S
BS
Shannon
Kevin
K
D019943:Amino Acid Substitution / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects; D002999:Clone Cells; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D051379:Mice; D018448:Models, Immunological; D050505:Mutant Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D050505:Mutant Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; C506614:mirdametinib; D004159:Diphenylamine; C045073:Cre recombinase; D019426:Integrases; D053829:Amyloid Precursor Protein Secretases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)