Mayukh Biswas

Assistant Professor

Education and Research Experience:

05/2022-06/2022: Postdoctoral Research Scientist, Department of Genetics and Development, Columbia University, New York, USA.

10/2020-04/2022: Postdoctoral Research Scientist, Institute for Cancer Genetics, Columbia University, New York, USA.

11/2019-09/2020: Staff Associate, Institute for Cancer Genetics, Columbia University, New York, USA.

07/2013-10/2019: Ph.D. in Cancer Biology, CSIR-Indian Institute of Chemical Biology (Degree awarded from the Dept. of Biotechnology, Jadavpur University).

07/2008-06/2013: Integrated M.Sc. in Biotechnology, St. Xavier’s College (Autonomous), Kolkata.

Awards:

2017: ASH Abstract Achievement Award at the 59th ASH Annual Meeting and Exposition (2017, Atlanta, USA) by American Society of Hematology.

2012: National Eligibility Test (NET- 2012 December) Fellowship in Life Sciences conducted jointly by Council of Scientific and Industrial Research (CSIR) and University Grants Commission (UGC), Govt. of India.

2013: Qualified GATE in Biotechnology (GATE-2013), organized by IIT Bombay.

Chromatin biology has never failed to amaze me and as a researcher my long-standing interest is to understand the plasticity associated with various epigenetic modifiers and their role in tumor initiation and progression in the context of hematologic malignancies. My academic training and research experience have provided me with a strong background in Epigenetics, Molecular and Cellular Biology and Biochemistry. During my Ph.D. I have worked on epigenetic regulation of hematopoietic stem cells in acute myeloid leukemia under the supervision of Dr. Amitava Sengupta at CSIR - Indian Institute of Chemical Biology (IICB), Kolkata. My study focused on elucidating and understanding the cellular and molecular mechanisms by which NuRD and SWI/SNF complexes regulate the epigenetic landscape of MDS and AML. In this project, I leveraged the analysis of primary patient samples to demonstrate a previously unrecognized major role of NuRD-mediated chromatin remodeling in AML and demonstrated that human myeloid leukemia frequently show loss of expression of specific NuRD subunits.

In addition, I demonstrated a direct interaction between NuRD and the histone demethylase KDM6A. This interaction in turn amplifies Rac GTPase-GEF DOCKs expression affecting leukemia cell trafficking and survival. These studies constituted the core of my thesis work “Nucleosome Remodeler Plasticity in Leukemic Hematopoiesis” at Jadavpur University, which I successfully defended in October 2020. In a separate project, I evaluated the role of SWI/SNF in AML and showed that SMARCB1 deficiency associates with nucleation of an altered SWI/SNF complex in human primary AML cells. In this context, loss of SMARCB1 induced recruitment of SWI/SNF and associated HATs to target GEFs for Rac GTPase activation and promoted AML cell migration. Collectively, these findings highlighted the tumor suppressor role of SMARCB1 and illustrated SWI/SNF function in maintaining an oncogenic gene expression program in AML.

I joined the laboratory of Dr. Adolfo Ferrando at the Institute for Cancer Genetics at Columbia University as a staff associate in November 2019 for my postdoctoral studies. The research program in the Ferrando lab seeks to identify and mechanistically dissect driver pathways involved in acute lymphoblastic leukemia (ALL) malignant proliferation and survival. Our group integrates genomic profiling, transcriptomics, biochemical assays, and animal models to functionally dissect the role of oncogenic and tumor suppressor transcription factors oncogenes, signaling factors and epigenetic regulators recurrently mutated in ALL. Following the identification of the Plant Homeodomain Finger 6 (PHF6) as a new X-linked tumor suppressor gene, the Ferrando lab established a primary role for PHF6 mutations in the initiation of T-ALL and demonstrated that PHF6 functions as an epigenetic regulator of long-term self-renewal in hematopoietic stem cells and leukemia initiating cell activity. My research program in the Ferrando lab aims to decipher the specific molecular mechanisms controlled by PHF6 using biochemical and state of the art proteomic, genetic and epigenetic analyses. The ultimate goal of these studies is to identify specific epigenetic mechanisms and collateral vulnerabilities associated with the loss of PHF6 in T-ALL.

Elucidation of the role of Chromatin Remodeling complexes in regulation of the epigenetic landscape in myeloid malignancies

Epigenetic reprogramming is implicated in tumor heterogeneity and oncogenic transformation. NuRD and SWI/SNF are major classes of ATP-dependent chromatin remodeling complexes present in the mammalian cells, regulating cell-fate commitment and transcriptional architecture and has important roles to play in development, genome integrity and cell cycle progression. Here we elucidated the role of NuRD and SWI/SNF in the pathogenesis of AML. In this project we have shown that in human primary AML cells, specific subunits of the NuRD complex are not expressed. NuRD complex interacts with the histone demethylase KDM6A resulting in increased Rac GTPase-GEF DOCKs expression, leukemia cell trafficking and survival. These results unveiled a novel link between chromatin remodelers NuRD and KDM6A in AML and pointed to DOCK inhibition as potential therapy in this disease. In another study we illustrated that human primary AML cells exhibit near complete loss of SMARCB1. This led to an increased recruitment of SWI/SNF and associated HATs to target loci, thereby promoting H3K27Ac and gene expression. Together, SMARCB1 deficiency induced GEFs for Rac GTPase activation and augmented AML cell migration and survival. Collectively, these findings highlight tumor suppressor role of SMARCB1 and illustrate SWI/SNF function in maintaining an oncogenic gene expression program in AML. In a separate study we profiled the gene expression signature of SWI/SNF complex in the HSC compartment of a cohort of patients diagnosed with Aplastic Anemia (AA). Our analysis identified a significant loss of the SWI/SNF core component SMARCC1, along with ARID1B, ACTL6A, and SMARCD1, in human AA BM CD34+ HSCs and HSPCs compared to normal counterpart. PBRM1, BRD7 and SMARCA2 expression were significantly upregulated in both untreated and follow-up AA patients. These findings illustrate for the first time SWI/SNF subunit expression heterogeneity in human AA HSPCs.

• Biswas M1, Chatterjee SS1, Boila LD, Chakraborty S, Banerjee D, Sengupta A. MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rac GTPase activation in human acute myeloid leukemia. FASEB J. 2019 Apr;33(4):5268-5286 (1Co-first authorship).
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• Chatterjee SS1, Biswas M1, Boila LD, Banerjee D, Sengupta A. SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Expression Program Maintenance in Human Acute Myeloid Leukemia. Mol Cancer Res. 2018 May;16(5):791-804 (1Co-first authorship).
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• Sinha S, Chatterjee SS, Biswas M, Nag A, Banerjee D, De R, Sengupta A. SWI/SNF Subunit Expression Heterogeneity in Human Aplastic Anemia Stem/Progenitors. Exp Hematol. 2018 Jun;62:39-44.e2.

Determination of the role of PHF6 in coupling chromatin remodeling, replication dynamics and DNA repair

The Plant Homeodomain Finger 6 gene (PHF6) encodes a nucleolar and chromatin-associated leukemia tumor suppressor with proposed roles in transcription regulation. Somatic mutations in PHF6 are highly recurrent in T-cell acute lymphoblastic leukemia (T-ALL) and biphentypic T-myeloid leukemias, where they are characteristically early lesions in leukemia transformation. In addition, PHF6 loss can be found in patients with preleukemic clonal hematopoiesis in support of a role for this tumor suppressor in leukemia initiation and hematopoietic stem cell (HSC) function. However, the specific molecular mechanisms mediating PHF6 tumor suppressor activity remain to be established. In this study we have demonstrated that PHF6 engages multiple nucleosome remodeling protein complexes including NuRD, SWI/SNF and ISWI factors, the replication machinery and DNA repair proteins. Moreover, following replicative stress-induced DNA damage, PHF6 localizes to sites of DNA injury and its loss impairs the resolution of DNA breaks with consequent accumulation of single- and double-stranded DNA lesions. We have illustrated that PHF6 specifically associates with difficult to replicate heterochromatin at satellite DNA regions enriched in H3K9me3 marks. Furthermore, PHF6 prevents unrestricted replication fork progression and single molecule locus-specific analyses identify PHF6 as an important regulator of genomic stability at fragile sites. These results extend our understanding of the molecular mechanisms controlling HSC homeostasis and leukemia transformation by placing PHF6 at the crossroads of chromatin remodeling, replicative fork dynamics and DNA repair.

• Alvarez S1, Almeida ACS1, Albero R, Biswas M, Barreto-Galvez A, Gunning TS, Shaikh A, Aparicio T, Wendorff A, Piovan E, Vlierberghe PV, Gygi S, Gautier J, Madireddy A, Ferrando AA. Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics and DNA repair. Blood. 2022 Jun 9;139(23):3418-3429.

Investigation of the role of Phf6 in HSC Aging

In the hematopoietic system, aging is characterized by accumulation of dysfunctional HSCs, which progressively become myeloid biased in their differentiation potential. Epigenetic alterations and genotoxic stress associated with age has been proposed to alter the self-renewal and differentiation capacity of aged HSCs. However, the underlying mechanisms driving these changes and their specific role in the control of the HSC aging program remain rudimentarily understood. Here we corroborated that genetic inactivation of the Phf6 gene antagonizes and effectively reverses age-associated HSC aging. Analysis of Phf6 knockout HSCs from old mice by immunophenotypic profiling, single cell transcriptomics and transplantation assays exhibited markedly decreased accumulation of HSCs, reduced myeloid bias and increased hematopoietic reconstitution capacity with preservation of lymphoid differentiation potential. In parallel, ablation of Phf6 in aged adult mice rewired the chromatin accessibility landscape and reversed immunophenotypic, transcriptional and functional hallmarks of HSC aging. These results identify Phf6 as an important epigenetic mediator of HSC aging, whose inactivation counters the functional deterioration of HSC activity associated with age.

• Wendorff AA1, Quinn SA1, Alvarez S, Brown JA, Biswas M, Gunning T, Palomero T, Ferrando AA. Epigenetic reversal of hematopoietic stem cell aging in Phf6 knockout mice. Nature Aging. 2022 Nov 10;2:1008-1023.

Interrogation of the role of KDM6A in DNA damage repair gene regulation in acute myeloid leukemia

KDM6A is a histone-3-lysine-27-demethylase that play context-dependent roles in AML, and we have identified it as a critical regulator of the DNA damage repair (DDR) gene expression programs. Mechanistically, KDM6 family protein expression is regulated by genotoxic stress and loss of both KDM6A (UTX) and KDM6B (JMJD3) impairs the DDR pathway compromising the repair potential. Accordingly, KDM6A-mutant human primary AML samples have increased susceptibility to Poly-(ADP-ribose)-polymerase (PARP) inhibition in vivo. Moreover, KDM6A loss increased both mitochondrial activity and BCL2 expression and downregulated BCL2A1 sensitizing AML cells to venetoclax. Substantiating the above results, targeting of both PARP and BCL2 was significantly more effective in inducing AML apoptosis compared to the treatments alone and primary AML cells carrying acquired KDM6A-domain mutations exhibited maximal sensitivity. Conclusively, our study illustrated a mechanistic rationale in support for a novel combination targeted therapy for human AML based on subtype heterogeneity and establishes KDM6A as an important molecular regulator for determining therapeutic efficacy.

• Boila LD, Ghosh S, Bandyopadhyay S, Lin L, Zeng AMA, Shaikh W, Bhowmik S, Muddineni SSNA, Biswas M, Sinha S, Chatterjee SS, Mbong N, Gan O, Bose A, Chakraborty S, Arruda A, Kennedy J, Mitchell A, Lechman E, Banerjee D, Milyavsky M, Minden M, Dick J, and Sengupta A. KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition. Leukemia. 2023 Jan 31. doi: 10.1038/s41375-023-01833-z.

Identification of the role of PBAF in orchestrating mesenchymal stromal signaling and lineage commitment

In this study we have elucidated the role of PBAF in integrating BMP/Smad signaling and osteogenic gene expression in mammalian MSC lineage commitment. We have shown that expression of Pbrm1, Arid2, and Brd7 were significantly upregulated by short-term BMP/Smad signaling as well as long-term osteogenic signals in murine and human primary MSCs. We have illustrated that osteogenic gene expression and osteolineage differentiation was impaired by the loss of Pbrm1/PBAFs via a de-regulation of BMP-dependent Smad1/5/8 activation pathway, and Pbrm1 loss hindered the expression of critical hematopoietic microenvironment/niche factors, resulting in a defective non-cell autonomous support of HSPC activity.

• Sinha S, Biswas M1, Chatterjee SS1, Kumar S, Sengupta A. Pbrm1 Steers Mesenchymal Stromal Cell Osteolineage Differentiation by Integrating PBAF-Dependent Chromatin Remodeling and BMP/TGF-β Signaling. Cell Rep. 2020 Apr 28;31(4):107570 (1Co-authorship).

Defining the role of RNA binding proteins in myelopoiesis and leukemic transformation

Here we have systematically utilized high-throughput transcriptomic data to identify RBPs regulating myelopoiesis. We analyzed the expression data of 1734 RBPs in the various HSC compartments and validated them to identify an oncogenic signature suggesting the dependency of LSCs on altered ribosome dynamics to maintain a cancer-specific translatome and their importance as potential candidates for therapeutic intervention.

• Saha S1, Murmu KC1, Biswas M, Chakraborty S, Basu J, Madhulika S, Kolkapalli SP, Chauhan S, Sengupta A, Prasad P. Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and Leukemia. Front Oncol. 2019 Aug 6;9:692.

As a kid I was always fascinated by the different diseases that create a havoc in the mankind and my long-standing interest has been to identify the cause and the root of these diseases and find ways to cure them. This led me to study cancer biology in depth and pursue research in the field of Leukemia. The passion and zeal to make students appreciate the beauty of science and in-depth understanding of the biology behind human diseases and its associated pathways and encourage them to pursue a scientific career has been one of my main driving forces among many. I think at the end of the day the job of a teacher is not only to make students memorize things, but make them inquisitive of things around them, teach them how to think deep, and motivate them to contribute scientifically for the benefit of society. In pursuit of this, I extensively teach masters students at the Institute of Health Sciences, Presidency University in the areas encompassing:

i) Biochemistry

ii) Molecular and cellular biology

iii) Epigenetics

iv) Enzymology

v) Genomics (and)

vi) Proteomics

Calcutta Consortium of Human Genetics (CCHuGe) [Life Member]

Peer-Reviewed Articles:

1.     Boila LD, Ghosh S, Bandyopadhyay S, Lin L, Zeng AMA, Shaikh W, Bhowmik S, Muddineni SSNA, Biswas M, Sinha S, Chatterjee SS, Mbong N, Gan O, Bose A, Chakraborty S, Arruda A, Kennedy J, Mitchell A, Lechman E, Banerjee D, Milyavsky M, Minden M, Dick J, and Sengupta A. KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition. Leukemia. 2023 Apr;37(4):751-764.

2.     Wendorff AA1, Quinn SA1, Alvarez S, Brown JA, Biswas M, Gunning T, Palomero T, Ferrando AA. Epigenetic reversal of hematopoietic stem cell aging in Phf6 knockout mice. Nature Aging. 2022 Nov 10;2:1008-1023.

3.     Alvarez S1, Almeida ACS1, Albero R, Biswas M, Barreto-Galvez A, Gunning TS, Shaikh A, Aparicio T, Wendorff A, Piovan E, Vlierberghe PV, Gygi S, Gautier J, Madireddy A, Ferrando AA. Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics and DNA repair. Blood. 2022 Jun 9;139(23):3418-3429.

4.     Sinha S, Biswas M1, Chatterjee SS1, Kumar S, Sengupta A. Pbrm1 Steers Mesenchymal Stromal Cell Osteolineage Differentiation by Integrating PBAF-Dependent Chromatin Remodeling and BMP/TGF-β Signaling. Cell Rep. 2020 Apr 28;31(4):107570. (1Co-authorship).

5.     Biswas M1, Chatterjee SS1, Boila LD, Chakraborty S, Banerjee D, Sengupta A. MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rac GTPase activation in human acute myeloid leukemia. FASEB J. 2019 Apr;33(4):5268-5286. (1Co-first authorship).

6.     Saha S1, Murmu KC1, Biswas M, Chakraborty S, Basu J, Madhulika S, Kolkapalli SP, Chauhan S, Sengupta A, Prasad P. Transcriptomic Analysis Identifies RNA Binding Proteins as Putative Regulators of Myelopoiesis and Leukemia. Front Oncol. 2019 Aug 6;9:692.

7.     Chatterjee SS1, Biswas M1, Boila LD, Banerjee D, Sengupta A. SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Expression Program Maintenance in Human Acute Myeloid Leukemia. Mol Cancer Res. 2018 May;16(5):791-804. (1Co-first authorship).

8.     Sinha S, Chatterjee SS, Biswas M, Nag A, Banerjee D, De R, Sengupta A. SWI/SNF Subunit Expression Heterogeneity in Human Aplastic Anemia Stem/Progenitors. Exp Hematol. 2018 Jun;62:39-44.e2.

Conference Publications:

1. Biswas M1, Chatterjee SS1, Boila LD, Chakraborty S, Banerjee D, Sengupta A. MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rac GTPase activation in human acute myeloid leukemia. International Symposium on Frontiers in Development and Molecular Medicine: Models to Insights, 2019, IICB-Translational Research Unit of Excellence (IICB-TRUE), CSIR-Indian Institute of Chemical Biology, Kolkata, India.

2. Chatterjee SS1, Biswas M1, Boila LD, Banerjee D, Sengupta A. SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Expression Program Maintenance in Human Acute Myeloid Leukemia. International Symposium on Frontiers in Development and Molecular Medicine: Models to Insights, 2019, IICB-Translational Research Unit of Excellence (IICB-TRUE), CSIR-Indian Institute of Chemical Biology, Kolkata, India.

3. Chatterjee SS1, Biswas M1, Boila LD, Chakraborty S, Sinha S, Banerjee D, Sengupta A. UTX and MBD3 epistasis regulates Rac GTPase activation and sensitizes human acute myeloid leukemia cells to DOCK inhibition. ASH Annual Meeting, 2018, San Diego, California, USA.

4. Chatterjee SS1, Biswas M1, Sengupta A. Transcriptional Cooperativity between SWI/SNF and NuRD Chromatin Remodelers in Acute Myeloid Leukemia. 47th Annual Scientific Meeting of International Society for Experimental Hematology, 2018, UCLA, Los Angeles, California, USA.

5. Chatterjee SS1, Biswas M1, Sengupta A. SWI/SNF and NuRD Chromatin Remodelers Display Transcriptional Cooperation in Myeloid Malignancies. SINP International Cancer Meeting 2018, Cancer Biology: Still A Challenge In 21st Century & SINP School On Epigenetics, Saha Institute of Nuclear Physics, Kolkata, India.

6. Biswas M1, Chatterjee SS1, Boila LD, Banerjee D, Sengupta A. Epigenetic Plasticity in ATP-Dependent Chromatin Remodeling Complexes in Human Acute Myeloid Leukemia. Indo-Japan Conference on Epigenetics and Human Disease, 2018, Bose Institute, Kolkata, India.

7. Biswas M1, Chatterjee SS1, Boila LD, Banerjee D, Sengupta A. Epigenetic Plasticity in ATP-Dependent Chromatin Remodeling Complexes in Human Acute Myeloid Leukemia. 59th American Society of Hematology (ASH) Annual Meeting & Exposition: Disordered Gene Expression in Hematologic Malignancy, including Disordered Epigenetic Regulation (602), 2017, Georgia World Congress Center, Atlanta, Georgia, USA.

8. Biswas M1, Chatterjee SS1, Boila LD, Sinha S, Chakraborty S, Banerjee D, Sengupta A. NuRD plasticity in human myelodysplasia/acute myeloid leukemia stem/progenitor cells. Keystone Symposia Conference: Hematopoiesis (B1), 2017, Fairmont Banff Springs, Banff, Alberta, Canada.

9. Biswas M1, Chatterjee SS1, Boila LD, Sinha S, Chakraborty S, Banerjee D, Sengupta A. Nucleosome remodelers in pre/leukemic hematopoiesis. 19th Transcription Assembly Meeting, 2016, Bose Institute, Kolkata, India.

10. Chatterjee SS1, Biswas M1, Boila LD, Sinha S, Chakraborty S, Banerjee D, Sengupta A. SWI/SNF chromatin remodelers in human hematopoietic stem/progenitor cell activity. Keystone Symposia Conference: Chromatin & Epigenetics (C2), 2016, Whistler Conference Center, Whistler, British Columbia, Canada.

11. Chatterjee SS1, Biswas M1, Boila LD, Sinha S, Chakraborty S, Banerjee D, Sengupta A. Deciphering chromatin remodeling in Myelodysplastic Syndrome. A Conference of New Ideas in Cancer: Challenging Dogmas, 2016, Tata Memorial Center, Mumbai, India.

12. Biswas M1, Chatterjee SS1, Boila LD, Sinha S, Chakraborty S, Banerjee D, Sengupta A. Hematopoietic stem and progenitor cell-autonomous epigenetic dysregulation in myeloid leukemia. 2nd Indian Society of Hematology & Blood Transfusion (ISHBT) & European Hematology Association (EHA), 2016, Mumbai, India.

13. Boila LD, Biswas M, Chatterjee SS, Saha S, Banerjee D, Sengupta A. Understanding Polycomb-mediated Hox gene regulation in hematopoietic stem cell and progenitor transformation in leukemia. EMBO Workshop, 2014, Upstream and Downstream of Hox genes. CCMB, Hyderabad, India.