As a physician scientist, I am particularly motivated by work that has the potential to improve public health, by advancing understanding of cancer for the eventual development of improved therapeutics. I hope to translate the knowledge gained from the experimental studies into effective therapy. My long-term goal is to improve cancer cure rates by developing novel therapeutics. To meet this challenge, I have been studying T-cell acute lymphoblastic leukemia (T-ALL) and other lymphoid malignancies.

T-ALL is a malignant disorder resulting from the leukemic transformation of T-cell precursors and is one of the most common forms of cancer in children and also found in adults. The most frequent genetic abnormality in T-ALL is the dysregulation of transcription factor genes, including aberrant expressions of TAL1, HOX11 and HOX11L2, and activating mutations of NOTCH1. However, those factors are generally difficult to target with small-molecules. Therefore, further advances in treatment outcome will require an improved knowledge of T-ALL.

“Core regulatory circuits” – We previously reported that the oncogenic transcription factor TAL1 and its regulatory partners (GATA3. RUNX1 and MYB) form a stem cell-like transcriptional circuitry in T-ALL cells. This discovery is significant, because it showed, for the first time, that cancer/leukemia cells possess the same general transcriptional network motifs that control the pluripotency and self-renewal of stem cells. Hence, we hypothesize that this regulatory structure we identified in T-ALL cells is likely required for the initiation or maintenance of malignant T-cells (“core regulatory circuits”).

Alteration of transcriptional regulatory program – Importantly, TAL1 is normally expressed in hematopoietic stem cells and regulates genes required for stem cell function, but it is silenced during T-cell development. Ectopic expression of TAL1 in immature thymocytes causes T-ALL. Hence, we think that TAL1 blocks the expression of genes that are normally required for T-cell differentiation and instead reactivates stem cell genes in malignant T-cells (“hijacking the stemness”), thus altering the transcriptional program in developing thymocytes. Such imbalance between T-cell differentiation and stem cell machineries would be the critical mechanism in T-ALL.

In our laboratory, we will elucidate the oncogenic mechanisms induced by the TAL1 complex in T-ALL cells and develop a novel means to target this machinery through combining cancer genomics with functional genetics and bioinformatics. We utilize the zebrafish model for functional analysis in vivo. Success in the projects will not only validate the therapeutic approach outlined above, but should also generate a series of highly effective, first-in-class small-molecule inhibitors for future clinical testing. The knowledge gleaned from this work could well extend to other leukemia/cancer in which an oncogenic transcription factor controls the core transcriptional machinery.

1. Wong RWJ, Tan TK, Amanda S, Ngoc PCT, Leong WZ, Tan SH, Asamitsu K, Hibi Y, Ueda R, Okamoto T, Ishida T, Iida S, Sanda T, Feed-forward Regulatory Loop Driven by IRF4 and NF-?B in Adult T-cell Leukemia/Lymphoma, Blood, in press.

2. Wang L, Tan TK, Durbin AD, Zimmerman MW, Abraham BJ, Tan SH, Ngoc PCT, Weichert N, Akahane K, Lawton LN, Rokita JL, Maris JM, Young RA, Look AT, Sanda T, ASCL1 is a MYCN- and LMO1-dependent member of the neuroblastoma adrenergic core regulatory circuitry, Nat Commun. 2019 Dec 9;10(1):5622.

3. Tan SH, Leong WZ, Ngoc PCT, Tan TK, Bertulfo FC, Lim MC, An O, Li Z, Yeoh AEJ, Fullwood MJ, Tenen DG and Sanda T. The enhancer RNA ARIEL activates the oncogenic transcriptional program in T-cell acute lymphoblastic leukemia. Blood. 2019 Jul 18;134(3):239-251

4. Ngoc PC, Tan SH, Tan TK, Chan MM, Li Z, Yeoh AEJ, Tenen DG, Sanda T. Identification of novel lncRNAs regulated by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia, 2018, Oct;32(10):2138-2151.

5. Leong WZ, Tan SH, Ngoc PCT, Amanda S, Yam AWY, Liau WS, Gong Z, Lawton LN, Tenen DG, Sanda T. ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis. Genes Dev. 2017 Dec 1;31(23-24):2343-2360.

6. Wong RWJ, Ngoc PCT, Leong WZ, Yam AWY, Zhang T, Asamitsu K, Iida S, Okamoto T, Ueda R, Gray NS, Ishida T, Sanda T. Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia. Blood. 2017 Nov 23;130(21):2326-2338

7. Liau WS, Tan SH, Ngoc PC, Wang CQ, Tergaonkar V, Feng H, Gong Z, Osato M, Look AT, Sanda T. Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia. Leukemia, 2017, Aug;31(8):1798-1807.

8. Tan SH, Yam AW, Lawton LN, Wong RW, Young RA, Look AT, Sanda T. TRIB2 reinforces the oncogenic transcriptional program controlled by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia. 2016 Apr;30(4):959-62.

9. Sanda T, Lawton LN, Barrasa MI, Fan ZP, Kohlhammer H, Gutierrez A, Ma W, Tatarek J, Ahn Y, Kelliher MA, Jamieson CHM, Staudt LM, Young RA, and Look AT. Core transcriptional regulatory circuit controlled by the TAL1 complex in human T-cell acute lymphoblastic leukemia. Cancer Cell, 2012 Aug 14;22(2):209-21.

10. Sanda T, Li X, Gutierrez A, Ahn Y, Neuberg DS, O’Neil J, Strack PR, Winter CG, Winter SS, Larson RS, von Boehmer H & Look AT. Interconnecting Molecular Pathways in the Pathogenesis and Drug Sensitivity of T-cell Acute Lymphoblastic Leukemia, Blood, 2010 Mar 4;115(9):1735-45.