Victoria N. Jideonwo-Auman

Indiana University School of Medicine

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Reuben Kapur

Indiana University – Purdue University Indianapolis

Lisa Deng

University of Freiburg

Rebecca J. Chan

Stanford University

Baskar Ramdas

Indiana University School of Medicine

Roshni Patel

Jesse Brown VA Medical Center

Briana M. Richine

Indiana University – Purdue University Indianapolis

Elizabeth L. Virts

Indiana University – Purdue University Indianapolis

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Indiana University School of Medicine

Indiana University – Purdue University Indianapolis

Indiana University

Perinatal Institute

Stanford University

University of Indianapolis

Center for Children

Indiana University Health

Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Laboratory of Molecular Genetics

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Rapid development of myeloproliferative neoplasm in mice with Ptpn11D61Y mutation and haploinsufficient for Dnmt3a

Oncotarget (2017)

Lisa Deng Briana M. Richine Elizabeth L. Virts Victoria N. Jideonwo-Auman Rebecca J. Chan

PTPN11 gain-of-function mutation is the most common mutation found in patients with juvenile myelomonocytic leukemia and DNMT3A loss occurs in over 20% of acute myeloid leukemia patients. We studied the combined effect of both Ptpn11 gain-of-function mutation (D61Y) and Dnmt3a haploinsufficiency on mouse hematopoiesis, the presence of which has been described in both juvenile myelomonocytic leukemia and acute myeloid leukemia patients. Double mutant mice rapidly become moribund relative to any of the other genotypes, which is associated with enlargement of the spleen and an increase in white blood cell counts. An increase in the mature myeloid cell compartment as reflected by the presence of Gr1+Mac1+ cells was also observed in double mutant mice relative to any other group. Consistent with these observations, a significant increase in the absolute number of granulocyte macrophage progenitors (GMPs) was seen in double mutant mice. A decrease in the lymphoid compartment including both T and B cells was noted in the double mutant mice. Another significant difference was the presence of extramedullary erythropoiesis with increased erythroid progenitors in the spleens of Dnmt3a+/-;D61Y mice relative to other groups. Taken together, our results suggest that the combined haploinsufficiency of Dnmt3a and presence of an activated Shp2 changes the composition of multiple hematopoietic lineages in mice relative to the individual heterozygosity of these genes.

Haploinsufficiency

Juvenile myelomonocytic leukemia

PTPN11

Leukocytosis

Monocytosis

Myeloproliferative Disorders

Myeloproliferative neoplasm

10.18632/oncotarget.23680

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Citations (5)

Combined Pharmacological Inhibition of Bruton's Tyrosine Kinase (BTK) and Phosphoinositide 3-Kinase (PI3K) p110δ Rescues Monocytosis, Thrombocytopenia, and Splenomegaly in a Genetic Mouse Model for JMML

Blood (2018)

Roshni Patel Baskar Ramdas Lisa Deng Victoria N. Jideonwo-Auman Rebecca J. Chan

Juvenile myelomonocytic leukemia

PTPN11

Idelalisib

10.1182/blood-2018-99-118802

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Citations (0)

Combined inhibition of Bruton’s Tyrosine Kinase (BTK) and Phosphoinositide 3-kinase (PI3K) p110δ improves monocytosis and splenomegaly in a JMML Mouse Model

Proceedings of IMPRS (2018)

Roshni Patel Baskar Ramdas Lisa Deng Victoria N. Jideonwo-Auman Reuben Kapur

Background and Hypothesis: Juvenile myelomonocytic leukemia (JMML) is an aggressive, childhood leukemic disorder for which there are no efficacious chemotherapeutics. Gain-of-function (GOF) mutations in the SHP2 phosphatase oncogene, Ptpn11, are the most common associated mutations. In hematopoietic cells, these mutations lead to increased AKT and ERK activation, which results in hyperproliferation of myeloid cells. Clinically, this manifests as monocytic leukocytosis and marked splenomegaly with the consequence of severe thrombocytopenia. Previously, this lab has shown that pharmacological inhibition of p110d, the hematopoietic-specific catalytic subunit of PI3K, moderates monocytosis and splenomegaly in a JMML mouse model with a SHP2 GOF mutation (E76K mice). Additionally, BTK has been identified as a potential therapeutic target as it cooperates with PI3K to increase activation of AKT and ERK in myeloid cells. Using a dual-hit approach of targeting both PI3K p110d and BTK may serve as a valuable treatment design for JMML. Experimental Design or Project Methods: We have treated E76K mice with a combination of 20mg/kg ACP319, a PI3K p110d-specific inhibitor, and 20mg/kg acalabrutinib, a BTK-specific inhibitor, via oral gavage twice daily for 21 days and performed hematopoietic analysis including the degree of splenomegaly, monocytosis, and thrombocytopenia. Results: The combination treatment scheme significantly decreased monocytosis and ameliorated thrombocytopenia compared to vehicle treated mice. Furthermore, splenomegaly was significantly reduced in the combination-treated mice compared to vehicle. Conclusion and Potential Impact: Combination chemotherapy with PI3K p110d- and BTK-specific inhibitors profoundly corrects disease state hallmarks of JMML, and may warrant further clinical investigation of efficacy.

Monocytosis

Phosphoinositide 3-kinase

10.18060/22825

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Citations (0)

Rapid development of myeloproliferative neoplasm in mice with Ptpn11D61Y mutation and haploinsufficient for Dnmt3a

PMC (2017)

Lisa Deng Briana M. Richine Elizabeth L. Virts Victoria N. Jideonwo-Auman Rebecca J. Chan

Haploinsufficiency

Juvenile myelomonocytic leukemia

Leukocytosis

Myeloproliferative Disorders