IU Indianapolis ScholarWorks :: Browsing by Author "Pasupuleti, Santhosh Kumar"

Browsing by Author "Pasupuleti, Santhosh Kumar"

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Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia
(The American Society for Clinical Investigation, 2024-06-17) Ramdas, Baskar; Dayal, Neetu; Pandey, Ruchi; Larocque, Elizabeth; Kanumuri, Rahul; Pasupuleti, Santhosh Kumar; Liu, Sheng; Kanellopoulou, Chrysi; Chu, Elizabeth Fei Yin; Mohallem, Rodrigo; Virani, Saniya; Chopra, Gaurav; Aryal, Uma K.; Lapidus, Rena; Wan, Jun; Emadi, Ashkan; Haneline, Laura S.; Holtsberg, Frederick W.; Aman, M. Javad; Sintim, Herman O.; Kapur, Reuben; Pediatrics, School of Medicine
Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.
Combined heterozygosity of FLT3 ITD, TET2, and DNMT3A results in aggressive leukemia
(The American Society for Clinical Investigation, 2022-09-08) Ramdas, Baskar; Reddy, Palam Lakshmi; Mali, Raghuveer Singh; Pasupuleti, Santhosh Kumar; Zhang, Ji; Kelley, Mark R.; Paczesny, Sophie; Zhang, Chi; Kapur, Reuben; Pediatrics, School of Medicine
Heterozygous mutations in FLT3ITD, TET2, and DNMT3A are associated with hematologic malignancies in humans. In patients, cooccurrence of mutations in FLT3ITD combined with TET2 (TF) or FLT3ITD combined with DNMT3A (DF) are frequent. However, in some rare complex acute myeloid leukemia (AML), all 3 mutations cooccur - i.e., FLT3ITD, TET2, and DNMT3A (TFD). Whether the presence of these mutations in combination result in quantitative or qualitative differences in disease manifestation has not been investigated. We generated mice expressing heterozygous Flt3ITD and concomitant for either heterozygous loss of Tet2 (TF) or Dnmt3a (DF) or both (TFD). TF and DF mice did not induce disease early on, in spite of similar changes in gene expression; during the same time frame, an aggressive form of transplantable leukemia was observed in TFD mice, which was mostly associated with quantitative but not qualitative differences in gene expression relative to TF or DF mice. The gene expression signature of TFD mice showed remarkable similarity to the human TFD gene signature at the single-cell RNA level. Importantly, TFD-driven AML responded to a combination of drugs that target Flt3ITD, inflammation, and methylation in a mouse model, as well as in a PDX model of AML bearing 3 mutations.
Driver Mutations in Leukemia Promote Disease Pathogenesis through a Combination of Cell-Autonomous and Niche Modulation
(Elsevier, 2020-07-14) Ramdas, Baskar; Mali, Raghuveer Singh; Palam, Lakshmi Reddy; Pandey, Ruchi; Cai, Zhigang; Pasupuleti, Santhosh Kumar; Burns, Sarah S.; Kapur, Reuben; Pediatrics, School of Medicine
Studies of patients with acute myeloid leukemia (AML) have led to the identification of mutations that affect different cellular pathways. Some of these have been classified as preleukemic, and a stepwise evolution program whereby cells acquire additional mutations has been proposed in the development of AML. How the timing of acquisition of these mutations and their impact on transformation and the bone marrow (BM) microenvironment occurs has only recently begun to be investigated. We show that constitutive and early loss of the epigenetic regulator, TET2, when combined with constitutive activation of FLT3, results in transformation of chronic myelomonocytic leukemia-like or myeloproliferative neoplasm-like phenotype to AML, which is more pronounced in double-mutant mice relative to mice carrying mutations in single genes. Furthermore, we show that in preleukemic and leukemic mice there are alterations in the BM niche and secreted cytokines, which creates a permissive environment for the growth of mutation-bearing cells relative to normal cells.
Editorial: Advanced neural stem cell therapies for spinal cord injury
(Frontiers Media, 2024-08-06) Katari, Venkatesh; Pasupuleti, Santhosh Kumar; Mullick, Madhubanti; Reddy Lekkala, Vinod Kumar; Sen, Dwaipayan; Pediatrics, School of Medicine
Il-1r1 drives leukemogenesis induced by Tet2 loss
(Springer Nature, 2022-10) Burns, Sarah S.; Kumar, Ramesh; Pasupuleti, Santhosh Kumar; So, Kaman; Zhang, Chi; Kapur, Reuben; Pediatrics, School of Medicine
Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells
(Elsevier, 2022) Ramdas, Baskar; Yuen, Lisa Deng; Palam, Lakshmi Reddy; Patel, Roshini; Pasupuleti, Santhosh Kumar; Jideonwo, Victoria; Zhang, Ji; Maguire, Callista; Wong, Eric; Kanumuri, Rahul; Zhang, Chujing; Sandusky, George; Chan, Rebecca J.; Zhang, Chi; Stieglitz, Elliot; Haneline, Laura; Kapur, Reuben; Pediatrics, School of Medicine
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton’s tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment.
Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway
(The American Society for Clinical Investigation, 2023-05-08) Palam, Lakshmi Reddy; Ramdas, Baskar; Pickerell, Katelyn; Pasupuleti, Santhosh Kumar; Kanumuri, Rahul; Cesarano, Annamaria; Szymanski, Megan; Selman, Bryce; Dave, Utpal P.; Sandusky, George; Perna, Fabiana; Paczesny, Sophie; Kapur, Reuben; Pediatrics, School of Medicine
Loss-of-function mutations in the DNA methyltransferase 3A (DNMT3A) are seen in a large number of patients with acute myeloid leukemia (AML) with normal cytogenetics and are frequently associated with poor prognosis. DNMT3A mutations are an early preleukemic event, which - when combined with other genetic lesions - result in full-blown leukemia. Here, we show that loss of Dnmt3a in hematopoietic stem and progenitor cells (HSC/Ps) results in myeloproliferation, which is associated with hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway. PI3Kα/β or the PI3Kα/δ inhibitor treatment partially corrects myeloproliferation, although the partial rescue is more efficient in response to the PI3Kα/β inhibitor treatment. In vivo RNA-Seq analysis on drug-treated Dnmt3a-/- HSC/Ps showed a reduction in the expression of genes associated with chemokines, inflammation, cell attachment, and extracellular matrix compared with controls. Remarkably, drug-treated leukemic mice showed a reversal in the enhanced fetal liver HSC-like gene signature observed in vehicle-treated Dnmt3a-/- LSK cells as well as a reduction in the expression of genes involved in regulating actin cytoskeleton-based functions, including the RHO/RAC GTPases. In a human PDX model bearing DNMT3A mutant AML, PI3Kα/β inhibitor treatment prolonged their survival and rescued the leukemic burden. Our results identify a potentially new target for treating DNMT3A mutation-driven myeloid malignancies.
Obesity-induced inflammation exacerbates clonal hematopoiesis
(The American Society for Clinical Investigation, 2023-06-01) Pasupuleti, Santhosh Kumar; Ramdas, Baskar; Burns, Sarah S.; Palam, Lakshmi Reddy; Kanumuri, Rahul; Kumar, Ramesh; Pandhiri, Taruni Reddy; Dave, Utpal P.; Yellapu, Nanda Kumar; Zhou, Xinyu; Zhang, Chi; Sandusky, George E.; Yu, Zhi; Honigberg, Michael C.; Bick, Alexander G.; Griffin, Gabriel K.; Niroula, Abhishek; Ebert, Benjamin L.; Paczesny, Sophie; Natarajan, Pradeep; Kapur, Reuben; Medicine, School of Medicine
Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis of indeterminate potential (CHIP) is frequent in aging and involves the expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, the risk factors that contribute to CHIP-associated clonal hematopoiesis (CH) are poorly understood. Obesity induces a proinflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data for 47,466 individuals with validated CHIP in the UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in the waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1, and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and that a proinflammatory state could potentiate the progression of CHIP to more significant hematologic neoplasia. The calcium channel blockers nifedipine and SKF-96365, either alone or in combination with metformin, MCC950, or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP-mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in individuals with obesity.
Potential clinical use of azacitidine and MEK inhibitor combination therapy in PTPN11-mutated juvenile myelomonocytic leukemia
(Elsevier, 2023) Pasupuleti, Santhosh Kumar; Chao, Karen; Ramdas, Baskar; Kanumuri, Rahul; Palam, Lakshmi Reddy; Liu, Sheng; Wan, Jun; Annesley, Colleen; Loh, Mignon L.; Stieglitz, Elliot; Burke, Michael J.; Kapur, Reuben; Pediatrics, School of Medicine
Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm of childhood. The molecular hallmark of JMML is hyperactivation of the Ras/MAPK pathway with the most common cause being mutations in the gene PTPN11, encoding the protein tyrosine phosphatase SHP2. Current strategies for treating JMML include using the hypomethylating agent, 5-azacitidine (5-Aza) or MEK inhibitors trametinib and PD0325901 (PD-901), but none of these are curative as monotherapy. Utilizing an Shp2E76K/+ murine model of JMML, we show that the combination of 5-Aza and PD-901 modulates several hematologic abnormalities often seen in JMML patients, in part by reducing the burden of leukemic hematopoietic stem and progenitor cells (HSC/Ps). The reduced JMML features in drug-treated mice were associated with a decrease in p-MEK and p-ERK levels in Shp2E76K/+ mice treated with the combination of 5-Aza and PD-901. RNA-sequencing analysis revealed a reduction in several RAS and MAPK signaling-related genes. Additionally, a decrease in the expression of genes associated with inflammation and myeloid leukemia was also observed in Shp2E76K/+ mice treated with the combination of the two drugs. Finally, we report two patients with JMML and PTPN11 mutations treated with 5-Aza, trametinib, and chemotherapy who experienced a clinical response because of the combination treatment.
Targeting SHP2 phosphatase in hematological malignancies
(Taylor & Francis, 2022) Kanumuri, Rahul; Pasupuleti, Santhosh Kumar; Burns, Sarah S.; Ramdas, Baskar; Kapur, Reuben; Pediatrics, School of Medicine
Introduction: Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitously expressed, non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene. Gain-of-function (GOF) mutations in PTPN11 are associated with the development of various hematological malignancies and Noonan syndrome with multiple lentigines (NS-ML). Preclinical studies performed with allosteric SHP2 inhibitors and combination treatments of SHP2 inhibitors with inhibitors of downstream regulators (such as MEK, ERK, and PD-1/PD-L1) demonstrate improved antitumor benefits. However, the development of novel SHP2 inhibitors is necessary to improve the therapeutic strategies for hematological malignancies and tackle drug resistance and disease relapse. Areas covered: This review examines the structure of SHP2, its function in various signaling cascades, the consequences of constitutive activation of SHP2 and potential therapeutic strategies to treat SHP2-driven hematological malignancies. Expert opinion: While SHP2 inhibitors have exhibited promise in preclinical trials, numerous challenges remain in translation to the clinic, including drug resistance. Although PROTAC-based SHP2 degraders show better efficacy than SHP2 inhibitors, novel strategies need to be designed to improve SHP2-specific therapies in hematologic malignancies. Genome-wide CRISPR screening should also be used to identify molecules that confer resistance to SHP2 inhibitors. Targeting these molecules together with SHP2 can increase the target specificity and reduce drug resistance.

Browsing by Author "Pasupuleti, Santhosh Kumar"

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