High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia.
Activating NOTCH1 mutations are frequent in human T-cell acute lymphoblastic leukemia (T-ALL) and Notch inhibitors (γ-secretase inhibitors [GSIs]) have produced responses in patients with relapsed, refractory disease. However, sustained responses, although reported, are uncommon, suggesting that other pathways can substitute for Notch in T-ALL. To address this possibility, we first generated KrasG12Dtransgenic mice with T-cell-specific expression of the pan-Notch inhibitor, dominant-negative Mastermind (DNMAML). These mice developed leukemia, but instead of accessing alternative oncogenic pathways, the tumor cells acquired Notch1 mutations and subsequently deleted DNMAML, reinforcing the notion that activated Notch1 is particularly transforming within the context of T-cell progenitors. We next took a candidate approach to identify oncogenic pathways downstream of Notch, focusing on Myc and Akt, which are Notch targets in T-cell progenitors. KrasG12Dmice transduced with Myc developed T-ALLs that were GSI-insensitive and lacked Notch1 mutations. In contrast, KrasG12Dmice transduced with myristoylated AKT developed GSI-sensitive T-ALLs that acquired Notch1 mutations. Thus, Myc can substitute for Notch1 in leukemogenesis, whereas Akt cannot. These findings in primary tumors extend recent work using human T-ALL cell lines and xenografts and suggest that the Notch/Myc signaling axis is of predominant importance in understanding both the selective pressure for Notch mutations in T-ALL and response and resistance of T-ALL to Notch pathway inhibitors.
Division of Hematology-Oncology, School of Medicine and.
Mark Y
0000-0003-2099-0956
MY
Chiang
Division of Hematology-Oncology, School of Medicine and.
Qing
Q
Wang
Cell and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI.
Anna C
AC
Gormley
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Institute of Medicine and Engineering, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; and.
Sarah J
SJ
Stein
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Institute of Medicine and Engineering, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; and.
Lanwei
L
Xu
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Institute of Medicine and Engineering, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; and.
Olga
O
Shestova
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Jon C
JC
Aster
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Institute of Medicine and Engineering, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; and.
Warren S
0000-0002-2624-0526
WS
Pear
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics*
C489428:Myc protein, mouse; C497762:Notch1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1
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