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Linda Chan, PhD

Research Scientist, Internal Medicine (Hematology)

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Linda Chan, PhD

Research Summary

By studying clinical outcome data to identify predictors of clinical outcomes in high-risk B-cell leukemia (COG P9906), Dr. Chan identified BCL6 as a novel therapeutic target in high-risk MLL-rearranged B-cell leukemia. In addition, her work on metabolic reprogramming in B-cell leukemia has helped establish a new paradigm of how B-lymphoid transcription factors repress glucose and energy supply to set low thresholds for negative selection of transformed B-cells based on energy stress. More recently, She investigated functional interactions of oncogenic genetic lesions across multiple signaling pathways in B-cell leukemia. Reflecting her keen interest in preclinical translational research, she developed an innovative therapeutic strategy based on pharmacological reactivation of divergent pathways to prevent drug resistance in B-cell leukemia.

Extensive Research Description

1. Metabolic gatekeeper functions of B-lymphoid transcription factors. B-lymphoid transcription factors (e.g. IKZF1 and PAX5) mediate B-cell lineage commitment; however, genetic lesions in B-lymphoid transcription factors are found in more than 80% of B-cell leukemia cases. Combining gene expression analysis with a CRISPR-based genetic screen, Dr. Chan discovered that B-lymphoid transcription factors unexpectedly function as metabolic gatekeepers to safeguard against transformation. Thus, the highly frequent genetic defects in B-lymphoid transcription factors in B-cell leukemia cases represent a critical mechanism to subvert functions of the metabolic gatekeepers to fuel leukemic transformation. In collaboration with other members of the laboratory of Dr. Markus Müschen, she identified energy abundance as central determinant of negative B-cell selection and sets the threshold for removal of pre-malignant clones. Furthermore, she contributed to the discovery of PP2A – a tumor suppressor in many types of cancer – as a unique vulnerability and potential therapeutic target in B-cell malignancies.

2. Feedback control of oncogenic signaling in B-cell malignancies as therapeutic target. Malignant transformation typically involves cooperation of multiple genetic lesions. On this basis, one would predict that acquisition of additional oncogenic lesions would promote tumorigenesis. However, by studying genetic interactions of oncogenic drivers across multiple signaling pathways in combination with single-cell mutation and phosphoprotein analyses of B-cell leukemia cases, Dr. Chan identified convergence on one principal oncogenic driver as a critical step in leukemia initiation and progression. In addition, she developed an innovative therapeutic approach based on pharmacological reactivation of the divergent pathway to prevent drug resistance and relapse. In collaboration with other members of the laboratory of Dr. Markus Müschen, she investigated genetic and small molecule modulation of oncogenic signaling pathways including PI3K/AKT and ERK and contributed to the discovery of feedback control of oncogenic signaling as therapeutic target in B-cell malignancies.

3. BCL6 represents a therapeutic target in high-risk MLL-rearranged B-cell leukemia. Chromosomal translocations involving the mixed lineage leukemia (MLL) gene account for ~10% of B-cell leukemia cases and are associated with dismal clinical outcomes with overall survival rates of <50%. Dr. Chan discovered MLL-dependent transactivation of BCL6 as a previously unrecognized requirement for MLL fusion-driven leukemic transformation. She devised a new therapeutic strategy for this disease based on combinatorial treatment with BCL6 inhibitor and BH3-mimetic ABT-199 (a BCL2-specific inhibitor).


Coauthors

Selected Publications

  • SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies.Leveille E, Chan LN, Mirza AS, Kume K, Müschen M. SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies. Cellular Signalling 2022, 94: 110331. PMID: 35398488, DOI: 10.1016/j.cellsig.2022.110331.
  • Metabolic Gatekeepers of Pathological B Cell Activation.Sadras T, Chan LN, Xiao G, Müschen M. Metabolic Gatekeepers of Pathological B Cell Activation. Annual Review Of Pathology 2021, 16: 323-349. PMID: 33321055, DOI: 10.1146/annurev-pathol-061020-050135.
  • PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis.Pan L, Hong C, Chan LN, Xiao G, Malvi P, Robinson ME, Geng H, Reddy ST, Lee J, Khairnar V, Cosgun KN, Xu L, Kume K, Sadras T, Wang S, Wajapeyee N, Müschen M. PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118 PMID: 33531346, PMCID: PMC7896313, DOI: 10.1073/pnas.2016553118.
  • R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis.Qing Y, Dong L, Gao L, Li C, Li Y, Han L, Prince E, Tan B, Deng X, Wetzel C, Shen C, Gao M, Chen Z, Li W, Zhang B, Braas D, Ten Hoeve J, Sanchez GJ, Chen H, Chan LN, Chen CW, Ann D, Jiang L, Müschen M, Marcucci G, Plas DR, Li Z, Su R, Chen J. R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis. Molecular Cell 2021, 81: 922-939.e9. PMID: 33434505, PMCID: PMC7935770, DOI: 10.1016/j.molcel.2020.12.026.
  • Author Correction: IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells.Lee J, Robinson ME, Ma N, Artadji D, Ahmed MA, Xiao G, Sadras T, Deb G, Winchester J, Cosgun KN, Geng H, Chan LN, Kume K, Miettinen TP, Zhang Y, Nix MA, Klemm L, Chen CW, Chen J, Khairnar V, Wiita AP, Thomas-Tikhonenko A, Farzan M, Jung JU, Weinstock DM, Manalis SR, Diamond MS, Vaidehi N, Müschen M. Author Correction: IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. Nature 2021, 592: E3. PMID: 33712811, DOI: 10.1038/s41586-021-03388-4.
  • Metabolic determinants of B-cell selection.Chan LN, Aghania E, Leveille E, Müschen M. Metabolic determinants of B-cell selection. Biochemical Society Transactions 2021, 49: 1467-1478. PMID: 34196360, DOI: 10.1042/BST20201316.
  • Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses.Contreras-Trujillo H, Eerdeng J, Akre S, Jiang D, Contreras J, Gala B, Vergel-Rodriguez MC, Lee Y, Jorapur A, Andreasian A, Harton L, Bramlett CS, Nogalska A, Xiao G, Lee JW, Chan LN, Müschen M, Merchant AA, Lu R. Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses. Nature Communications 2021, 12: 6522. PMID: 34764253, PMCID: PMC8586369, DOI: 10.1038/s41467-021-26771-1.
  • Signalling input from divergent pathways subverts B cell transformation.Chan LN, Murakami MA, Robinson ME, Caeser R, Sadras T, Lee J, Cosgun KN, Kume K, Khairnar V, Xiao G, Ahmed MA, Aghania E, Deb G, Hurtz C, Shojaee S, Hong C, Pölönen P, Nix MA, Chen Z, Chen CW, Chen J, Vogt A, Heinäniemi M, Lohi O, Wiita AP, Izraeli S, Geng H, Weinstock DM, Müschen M. Signalling input from divergent pathways subverts B cell transformation. Nature 2020, 583: 845-851. PMID: 32699415, PMCID: PMC7394729, DOI: 10.1038/s41586-020-2513-4.
  • IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells.Lee J, Robinson ME, Ma N, Artadji D, Ahmed MA, Xiao G, Sadras T, Deb G, Winchester J, Cosgun KN, Geng H, Chan LN, Kume K, Miettinen TP, Zhang Y, Nix MA, Klemm L, Chen CW, Chen J, Khairnar V, Wiita AP, Thomas-Tikhonenko A, Farzan M, Jung JU, Weinstock DM, Manalis SR, Diamond MS, Vaidehi N, Müschen M. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. Nature 2020, 588: 491-497. PMID: 33149299, PMCID: PMC8087162, DOI: 10.1038/s41586-020-2884-6.
  • Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia.Hurtz C, Chan LN, Geng H, Ballabio E, Xiao G, Deb G, Khoury H, Chen CW, Armstrong SA, Chen J, Ernst P, Melnick A, Milne T, Müschen M. Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia. Genes & Development 2019, 33: 1265-1279. PMID: 31395741, PMCID: PMC6719625, DOI: 10.1101/gad.327593.119.
  • B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies.Xiao G, Chan LN, Klemm L, Braas D, Chen Z, Geng H, Zhang QC, Aghajanirefah A, Cosgun KN, Sadras T, Lee J, Mirzapoiazova T, Salgia R, Ernst T, Hochhaus A, Jumaa H, Jiang X, Weinstock DM, Graeber TG, Müschen M. B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. Cell 2018, 173: 470-484.e18. PMID: 29551267, PMCID: PMC6284818, DOI: 10.1016/j.cell.2018.02.048.
  • Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL.Martín-Lorenzo A, Auer F, Chan LN, García-Ramírez I, González-Herrero I, Rodríguez-Hernández G, Bartenhagen C, Dugas M, Gombert M, Ginzel S, Blanco O, Orfao A, Alonso-López D, Rivas JL, García-Cenador MB, García-Criado FJ, Müschen M, Sánchez-García I, Borkhardt A, Vicente-Dueñas C, Hauer J. Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL. Cancer Research 2018, 78: 2669-2679. PMID: 29490943, PMCID: PMC6245574, DOI: 10.1158/0008-5472.CAN-17-3262.
  • Author Correction: Metabolic gatekeeper function of B-lymphoid transcription factors.Chan LN, Chen Z, Braas D, Lee JW, Xiao G, Geng H, Cosgun KN, Hurtz C, Shojaee S, Cazzaniga V, Schjerven H, Ernst T, Hochhaus A, Kornblau SM, Konopleva M, Pufall MA, Cazzaniga G, Liu GJ, Milne TA, Koeffler HP, Ross TS, Sánchez-García I, Borkhardt A, Yamamoto KR, Dickins RA, Graeber TG, Müschen M. Author Correction: Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 2018, 558: E5. PMID: 29849140, DOI: 10.1038/s41586-018-0164-5.
  • Metabolic gatekeeper function of B-lymphoid transcription factors.Chan LN, Chen Z, Braas D, Lee JW, Xiao G, Geng H, Cosgun KN, Hurtz C, Shojaee S, Cazzaniga V, Schjerven H, Ernst T, Hochhaus A, Kornblau SM, Konopleva M, Pufall MA, Cazzaniga G, Liu GJ, Milne TA, Koeffler HP, Ross TS, Sánchez-García I, Borkhardt A, Yamamoto KR, Dickins RA, Graeber TG, Müschen M. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 2017, 542: 479-483. PMID: 28192788, PMCID: PMC5621518, DOI: 10.1038/nature21076.
  • B-cell identity as a metabolic barrier against malignant transformation.Chan LN, Müschen M. B-cell identity as a metabolic barrier against malignant transformation. Experimental Hematology 2017, 53: 1-6. PMID: 28655536, PMCID: PMC5568490, DOI: 10.1016/j.exphem.2017.06.004.
  • PTEN opposes negative selection and enables oncogenic transformation of pre-B cells.Shojaee S, Chan LN, Buchner M, Cazzaniga V, Cosgun KN, Geng H, Qiu YH, von Minden MD, Ernst T, Hochhaus A, Cazzaniga G, Melnick A, Kornblau SM, Graeber TG, Wu H, Jumaa H, Müschen M. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nature Medicine 2016, 22: 379-87. PMID: 26974310, PMCID: PMC5178869, DOI: 10.1038/nm.4062.
  • Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia.Geng H, Hurtz C, Lenz KB, Chen Z, Baumjohann D, Thompson S, Goloviznina NA, Chen WY, Huan J, LaTocha D, Ballabio E, Xiao G, Lee JW, Deucher A, Qi Z, Park E, Huang C, Nahar R, Kweon SM, Shojaee S, Chan LN, Yu J, Kornblau SM, Bijl JJ, Ye BH, Ansel KM, Paietta E, Melnick A, Hunger SP, Kurre P, Tyner JW, Loh ML, Roeder RG, Druker BJ, Burger JA, Milne TA, Chang BH, Müschen M. Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia. Cancer Cell 2015, 27: 409-25. PMID: 25759025, PMCID: PMC4618684, DOI: 10.1016/j.ccell.2015.02.003.
  • Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia.Shojaee S, Caeser R, Buchner M, Park E, Swaminathan S, Hurtz C, Geng H, Chan LN, Klemm L, Hofmann WK, Qiu YH, Zhang N, Coombes KR, Paietta E, Molkentin J, Koeffler HP, Willman CL, Hunger SP, Melnick A, Kornblau SM, Müschen M. Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia. Cancer Cell 2015, 28: 114-28. PMID: 26073130, PMCID: PMC4565502, DOI: 10.1016/j.ccell.2015.05.008.
  • Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia.Kharabi Masouleh B, Geng H, Hurtz C, Chan LN, Logan AC, Chang MS, Huang C, Swaminathan S, Sun H, Paietta E, Melnick AM, Koeffler P, Müschen M. Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: E2219-28. PMID: 24821775, PMCID: PMC4040579, DOI: 10.1073/pnas.1400958111.
  • SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia.Ramezani-Rad P, Geng H, Hurtz C, Chan LN, Chen Z, Jumaa H, Melnick A, Paietta E, Carroll WL, Willman CL, Lefebvre V, Müschen M. SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. Blood 2013, 121: 148-55. PMID: 23152540, PMCID: PMC3538327, DOI: 10.1182/blood-2012-05-428938.
  • Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.Chan LN, Fiji HD, Watanabe M, Kwon O, Tamanoi F. Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I. PloS One 2011, 6: e26135. PMID: 22028818, PMCID: PMC3196516, DOI: 10.1371/journal.pone.0026135.
  • A novel approach to tag and identify geranylgeranylated proteins.Chan LN, Hart C, Guo L, Nyberg T, Davies BS, Fong LG, Young SG, Agnew BJ, Tamanoi F. A novel approach to tag and identify geranylgeranylated proteins. Electrophoresis 2009, 30: 3598-606. PMID: 19784953, PMCID: PMC2855049, DOI: 10.1002/elps.200900259.
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