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INFORMATION FOR

Manoj M Pillai, MBBS

Associate Professor of Medicine (Hematology)

Research Summary

Our group is interested in how Hematopoiesis (production of blood) is regulated at a molecular and biochemical level in normal and disease states. Hematopoiesis in the adult vertebrate is enormously complex and occurs within the specialized locations in the trabecular bone (variously called the hematopoietic niche or marrow microenvironment). Almost one trillion blood cells are formed each day in a normal human; each of these cells arise from a hematopoietic stem or progenitor cell (HSPC) after undergoing well regulated proliferation and differentiation. Cells in the microenvironment provide these regulatory signals. Our group is interested in implementing genome-wide biochemistry to better understand how blood cells progress from the HSPC to mature blood cells. These approaches are also being used to define hematopoietic dysregulation in diseases such as leukemia.

Extensive Research Description

1. Role of small RNAs, long non-coding RNAs and RNA binding proteins in marrow microenvironment.

The marrow microenvironment (ME) is comprised of several different subtypes including marrow stromal cells, macrophages, endothelial cells, osteoblasts etc. Various ligands critical to hematopoietic stem and progenitor cells (HSPC) are elaborated by several of these cells types. What is not known is how coordinated expression of these factors is effected across different cell types. We hypothesize that common themes of regulation of gene expression are operant through these cell types. We have implemented several genome-wide techniques including HITS-CLIP (High-throughput sequencing of RNA isolated by crosslinking immunoprecipitation) and RNA-Seq to define the role of small RNAs, long non-coding RNAs and RNA-biding proteins in this regulation. Studies are conducted in human stromal cell lines as well as primary human cells from healthy donors.

2. Biology Spliceosome Mutations in Myelodysplastic Syndromes (MDS).

MDS are a heterogeneous group of blood disorders characterized by clonal proliferation of hematopoietic progenitors and low blood counts. Recently, whole genome sequencing has revealed recurring mutations in the RNA-splicing machinery (SF3B1, U2AF1, SRSF2 etc) in up to half the patients with MDS. It is currently unclear how mutations in the highly conserved and ubiquitous splicing machinery can result in the specific phenotype of MDS. We are using a variety of in vivo and in vitro approaches to define the mechanistic basis of these mutations at the molecular, cellular and tissue levels.

3. Musashi Proteins in Aggressive Myeloid Leukemia.

The RNA binding protein Musashi 2 (MSI2) is transcriptionally upregulated in aggressive myeloid leukemia including CML-blast crises and some AML which are resistant to therapies. Although purported to bind to specific sequence motifs in 3’ UTRs of transcripts such as NUMB, unbiased studies have not suggested this to be the mechanism by which MSI2 function in the context of leukemia. Our laboratory is implementing unbiased genome-wide studies including HITS-CLIP to precisely define how MSI2 expression leads to chemoresistance.

Coauthors

Research Interests

Hematopoiesis; Hematopoietic Stem Cells; Myelodysplastic Syndromes; MicroRNAs; Cellular Microenvironment

Selected Publications

  • Complex Formation between FANCD2 and the Splicing Factor SRSF1 Helps Prevent R-Loop Accumulation through mRNA Export RegulationOlazabal Herrero A, Liang F, Dutta A, Huang Y, Liang Z, Gupta A, Lan L, Pillai M, Sung P, Kupfer G. Complex Formation between FANCD2 and the Splicing Factor SRSF1 Helps Prevent R-Loop Accumulation through mRNA Export Regulation Blood 2022, 140: 5828-5829. DOI: 10.1182/blood-2022-166798.
  • Fanci-FANCD2 Promotes Genome Stability and DNA Repair By Down-Regulating BLM Helicase ActivityLiang F, Nagarajan A, Pillai M, Sung P, Kupfer G. Fanci-FANCD2 Promotes Genome Stability and DNA Repair By Down-Regulating BLM Helicase Activity Blood 2021, 138: 1113-1113. DOI: 10.1182/blood-2021-152218.
  • 40008 COMBINED CRISPR/CAS9 AND AAV FOR THE GENERATION OF CONDITIONAL ISOGENIC GENE KNOCK-INSBoddu P, Gupta A, Waldman T, Pillai M. 40008 COMBINED CRISPR/CAS9 AND AAV FOR THE GENERATION OF CONDITIONAL ISOGENIC GENE KNOCK-INS Journal Of Clinical And Translational Science 2021, 5: 22-22. PMCID: PMC8827824, DOI: 10.1017/cts.2021.460.
  • Binding of FANCD2 to SRSF1 Splicing Factor Prevents Genomic Instability through R Loop RegulationOlazabal-Herrero A, Green A, Chen X, Sung P, Pillai M, Kupfer G. Binding of FANCD2 to SRSF1 Splicing Factor Prevents Genomic Instability through R Loop Regulation Blood 2020, 136: 19-19. DOI: 10.1182/blood-2020-141369.
  • Abstract 6333: Genomic, transcriptomic, and epigenetic profiling of triple-negative breast cancer cells after Navitoclax treatmentMarczyk M, Gunasekharan V, Zhao J, Qu R, Li X, Patwardhan G, Wali V, Gupta A, Pillai M, Kluger Y, Hatzis C, Pusztai L. Abstract 6333: Genomic, transcriptomic, and epigenetic profiling of triple-negative breast cancer cells after Navitoclax treatment Cancer Research 2020, 80: 6333-6333. DOI: 10.1158/1538-7445.am2020-6333.
  • Clinical Outcomes of Patients (pts) with TP53-Mutated Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS): A Single Center ExperienceBewersdorf J, Shallis R, Gowda L, Hager K, Podoltsev N, Gore S, Prebet T, Halene S, Isufi I, Foss F, Huntington S, Kim T, Pillai M, Parker T, Neparidze N, Bar N, Seropian S, Siddon A, Zeidan A. Clinical Outcomes of Patients (pts) with TP53-Mutated Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS): A Single Center Experience Blood 2019, 134: 5173-5173. DOI: 10.1182/blood-2019-127162.
  • Isolated Trisomy 11 in Patients with Myeloid Malignancies - Is the Prognosis Not As Grim As Previously Thought?Bewersdorf J, Shallis R, Diadamo A, Gowda L, Podoltsev N, Gore S, Prebet T, Halene S, Isufi I, Foss F, Huntington S, Kim T, Pillai M, Parker T, Neparidze N, Bar N, Seropian S, Siddon A, Zeidan A. Isolated Trisomy 11 in Patients with Myeloid Malignancies - Is the Prognosis Not As Grim As Previously Thought? Blood 2019, 134: 5174-5174. DOI: 10.1182/blood-2019-127277.
  • Immune Checkpoint Inhibitor Therapy for Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes: A Single-Center ExperienceShallis R, Bewersdorf J, Gowda L, Podoltsev N, Prebet T, Gore S, Halene S, Isufi I, Foss F, Huntington S, Kim T, Pillai M, Parker T, Neparidze N, Bar N, Seropian S, Zeidan A. Immune Checkpoint Inhibitor Therapy for Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes: A Single-Center Experience Blood 2019, 134: 1330-1330. DOI: 10.1182/blood-2019-127422.
  • U2AF1 Driver Mutations in Hematopoietic Disorders Alter but Do Not Abrogate RNA Binding and Enlighten Structural Dependencies of the U2AF-RNA ComplexBiancon G, Joshi P, Hunck T, Gao Y, Botti V, Qin A, Sadykov M, Wang X, Viero G, Neuenkirchen N, Taylor A, Huang J, Ardasheva A, Fu X, Lin H, Pillai M, Kielkopf C, Neugebauer K, Tebaldi T, Halene S. U2AF1 Driver Mutations in Hematopoietic Disorders Alter but Do Not Abrogate RNA Binding and Enlighten Structural Dependencies of the U2AF-RNA Complex Blood 2019, 134: 1230-1230. DOI: 10.1182/blood-2019-130759.
  • SF3B1 Mutations Induce Oncogenic IRAK4 Isoforms and Activate Targetable Innate Immune Pathways in MDS and AMLChoudhary G, Smith M, Pellagatti A, Bhagat T, Gordon S, Pandey S, Shah N, Aluri S, Booher R, Ramachandra M, Samson M, Pradhan K, Bowman T, Pillai M, Guha C, Wickrema A, Will B, Shastri A, Steidl U, Boultwood J, Starczynowski D, Verma A. SF3B1 Mutations Induce Oncogenic IRAK4 Isoforms and Activate Targetable Innate Immune Pathways in MDS and AML Blood 2019, 134: 4224-4224. DOI: 10.1182/blood-2019-124458.
  • Allogeneic Stem Cell Transplantation for T-Cell Lymphomas in the Modern Era: A Single Center ExperienceBoddu P, Perreault S, Isufi I, Chandhok N, Kim T, Pillai M, Bar N, Prebet T, Zeidan A, Zelterman D, Seropian S, Gowda L, Foss F. Allogeneic Stem Cell Transplantation for T-Cell Lymphomas in the Modern Era: A Single Center Experience Transplantation And Cellular Therapy 2019, 25: s387. DOI: 10.1016/j.bbmt.2018.12.796.
  • Restrictive Transfusions in the Era of Pathogen-Inactivated Platelets: A Single Center ExperienceShallis R, Gleeson S, Chokr N, Fangyong L, Wei W, Azar M, Schulz W, Summers D, Hendrickson J, Foss F, Isufi I, Kim T, Pillai M, Snyder E, Seropian S, Gowda L. Restrictive Transfusions in the Era of Pathogen-Inactivated Platelets: A Single Center Experience Transplantation And Cellular Therapy 2019, 25: s365. DOI: 10.1016/j.bbmt.2018.12.591.
  • Integrative Analysis of RNA-Interactome and Translatome Reveal Functional Targets of MSI2 in Myeloid LeukemiaRamirez O, Kesarwani A, Abhishek G, Minella A, Pillai M. Integrative Analysis of RNA-Interactome and Translatome Reveal Functional Targets of MSI2 in Myeloid Leukemia Blood 2016, 128: 1881-1881. DOI: 10.1182/blood.v128.22.1881.1881.
  • SF3B1 Interactions with Chromatin Are Dynamic and Regulated in a Cell Cycle-Dependent MannerMurthy T, Bluemn T, Pillai M, Minella A. SF3B1 Interactions with Chromatin Are Dynamic and Regulated in a Cell Cycle-Dependent Manner Blood 2016, 128: 1480-1480. DOI: 10.1182/blood.v128.22.1480.1480.
  • Integrative Genome-Wide Analysis of RNA Binding and Splicing Reveals Complex Loss and Gain of Function Alterations By SRSF2 P95 Mutations in MyelodysplasiaRejeski K, Liang Y, Tebaldi T, Stefani G, Taylor A, Maziarz J, Song Y, Balasubramanian K, Vasic R, Kapetanovic E, Abdel-Wahab O, Pillai M, Halene S. Integrative Genome-Wide Analysis of RNA Binding and Splicing Reveals Complex Loss and Gain of Function Alterations By SRSF2 P95 Mutations in Myelodysplasia Blood 2015, 126: 141-141. DOI: 10.1182/blood.v126.23.141.141.
  • Expression Of Mutant Spliceosomal Protein SF3B1 Results In Dysregulated Hematopoietic MaturationMinella A, Ramirez O, Xu Y, Murthy T, Yang X, Pillai M. Expression Of Mutant Spliceosomal Protein SF3B1 Results In Dysregulated Hematopoietic Maturation Blood 2013, 122: 2773-2773. DOI: 10.1182/blood.v122.21.2773.2773.
  • The Adult Stem Cell NicheRamakrishnan A, Pillai M, Torok-Storb B. The Adult Stem Cell Niche 2013, 15-30. DOI: 10.1007/978-1-4614-9569-7_2.
  • Abstract PD01-07: High throughput sequencing following cross-linked immune-precipitation (HITS-CLIP) of Argonaute protein reveals novel miRNA regulatory pathways of Estrogen Receptor in breast cancer.Kabos P, Kline E, Brown J, Flory K, Sartorius C, Hesselberth J, Pillai M. Abstract PD01-07: High throughput sequencing following cross-linked immune-precipitation (HITS-CLIP) of Argonaute protein reveals novel miRNA regulatory pathways of Estrogen Receptor in breast cancer. Cancer Research 2012, 72: pd01-07-pd01-07. DOI: 10.1158/0008-5472.sabcs12-pd01-07.
  • Marrow Stromal Cells (MSC) Rescue Hematopoiesis in Lethally Irradiated Mice Despite Rapid Clearance After Infusion,Yang X, Balakrishnan I, Torok-Storb B, Pillai M. Marrow Stromal Cells (MSC) Rescue Hematopoiesis in Lethally Irradiated Mice Despite Rapid Clearance After Infusion, Blood 2011, 118: 3406-3406. DOI: 10.1182/blood.v118.21.3406.3406.
  • High Throughput Sequencing Following Cross-Linked Immune Precipitation (HITS-CLIP) of Argonaute (AGO) Identifies Mir-9 As a Regulator of MMP2 in the Marrow Microenvironment (ME)Balakrishnan I, Yang X, Torok-Storb B, Hesselberth J, Pillai M. High Throughput Sequencing Following Cross-Linked Immune Precipitation (HITS-CLIP) of Argonaute (AGO) Identifies Mir-9 As a Regulator of MMP2 in the Marrow Microenvironment (ME) Blood 2011, 118: 2392-2392. DOI: 10.1182/blood.v118.21.2392.2392.
  • High Throughput Sequencing Following Cross-Linked Immune Precipitation (HITS-CLIP) of Argonaute (AGO) Identifies Mir-193a as a Regulator of Jagged1 In Marrow Stromal Cells.Balakrishnan I, Yang X, Torok-Storb B, Hesselberth J, Pillai M. High Throughput Sequencing Following Cross-Linked Immune Precipitation (HITS-CLIP) of Argonaute (AGO) Identifies Mir-193a as a Regulator of Jagged1 In Marrow Stromal Cells. Blood 2010, 116: 3847-3847. DOI: 10.1182/blood.v116.21.3847.3847.
  • Mir-886-3p Contributes to the Regulation of the hematopoietic microenvironment by down-Regulating SDF-1α (CXCL12).Pillai M, Yang X, Iwata M, Bemis L, Torok-Storb B. Mir-886-3p Contributes to the Regulation of the hematopoietic microenvironment by down-Regulating SDF-1α (CXCL12). Blood 2009, 114: 561-561. DOI: 10.1182/blood.v114.22.561.561.
  • Inducible Levels of Gelatinase B/Matrix Metalloproteinase-9 Gene Expression in Monocytes Are Associated with Marrow Cellularity in Myelodysplastic Syndrome (MDS).Iwata M, Pillai M, Deeg H, Opdenakker G, Torok-Storb B. Inducible Levels of Gelatinase B/Matrix Metalloproteinase-9 Gene Expression in Monocytes Are Associated with Marrow Cellularity in Myelodysplastic Syndrome (MDS). Blood 2005, 106: 1391-1391. DOI: 10.1182/blood.v106.11.1391.1391.
  • Human Marrow Stromal Cells Activate Monocytes to Secrete CXCL7 Peptides, Which Alter the Composition of the Hematopoietic Microenvironment (ME).Pillai M, Iwata M, Dahlen D, Torok-Storb B. Human Marrow Stromal Cells Activate Monocytes to Secrete CXCL7 Peptides, Which Alter the Composition of the Hematopoietic Microenvironment (ME). Blood 2004, 104: 668-668. DOI: 10.1182/blood.v104.11.668.668.