Abstract
Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) exhibits lymphoid, myeloid, and stem cell features and is associated with a poor prognosis. Whole genome sequencing of human ETP-ALL cases has identified recurrent mutations in signaling, histone modification, and hematopoietic development genes but it remains to be determined which of these abnormalities are sufficient to initiate leukemia. We show that activating mutations in the interleukin-7 receptor identified in human pediatric ETP-ALL cases are sufficient to generate ETP-ALL in mice transplanted with primitive transduced thymocytes from p19(Arf-/-) mice. The cellular mechanism by which these mutant receptors induce ETP-ALL is the block of thymocyte differentiation at the double negative 2 stage at which myeloid lineage and T lymphocyte developmental potential coexist. Analyses of samples from pediatric ETP-ALL cases and our murine ETP-ALL model show uniformly high levels of LMO2 expression, very low to undetectable levels of BCL11B expression, and a relative lack of activating NOTCH1 mutations. We report that pharmacological blockade of Jak-Stat signaling with ruxolitinib has significant antileukemic activity in this ETP-ALL model. This new murine model recapitulates several important cellular and molecular features of ETP-ALL and should be useful to further define novel therapeutic approaches for this aggressive leukemia.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / metabolism
-
Animals
-
Carcinogenesis / drug effects
-
Carcinogenesis / genetics
-
Cell Differentiation / drug effects
-
Cell Differentiation / genetics
-
Child
-
Disease Models, Animal
-
Gene Expression Regulation, Neoplastic / drug effects
-
Humans
-
Janus Kinases / metabolism
-
LIM Domain Proteins / metabolism
-
Mice
-
Multipotent Stem Cells / cytology*
-
Multipotent Stem Cells / drug effects
-
Multipotent Stem Cells / metabolism
-
Mutation / genetics*
-
Neoplasm Transplantation
-
Nitriles
-
Phenotype
-
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
-
Pyrazoles / pharmacology
-
Pyrazoles / therapeutic use
-
Pyrimidines
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Receptors, Interleukin-7 / genetics*
-
Receptors, Notch / metabolism
-
Repressor Proteins / metabolism
-
STAT Transcription Factors / metabolism
-
Signal Transduction / drug effects
-
Signal Transduction / genetics
-
Thymocytes / drug effects
-
Thymocytes / metabolism
-
Thymocytes / pathology*
-
Tumor Suppressor Proteins / metabolism
-
p38 Mitogen-Activated Protein Kinases / metabolism
Substances
-
Adaptor Proteins, Signal Transducing
-
Bcl11b protein, mouse
-
LIM Domain Proteins
-
Lmo2 protein, mouse
-
Nitriles
-
Pyrazoles
-
Pyrimidines
-
RNA, Messenger
-
Receptors, Interleukin-7
-
Receptors, Notch
-
Repressor Proteins
-
STAT Transcription Factors
-
Tumor Suppressor Proteins
-
ruxolitinib
-
Janus Kinases
-
p38 Mitogen-Activated Protein Kinases