Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

Bottomly D, Long N, Schultz AR, Kurtz SE, Tognon CE, Johnson K, Abel M, Agarwal A, Avaylon S, Benton E, Blucher A, Borate U, Braun TP, Brown J, Bryant J, Burke R, Carlos A, Chang BH, Cho HJ, Christy S, Coblentz C, Cohen AM, d'Almeida A, Cook R, Danilov A, Dao KT, Degnin M, Dibb J, Eide CA, English I, Hagler S, Harrelson H, Henson R, Ho H, Joshi SK, Junio B, Kaempf A, Kosaka Y, Laderas T, Lawhead M, Lee H, Leonard JT, Lin C, Lind EF, Liu SQ, Lo P, Loriaux MM, Luty S, Maxson JE, Macey T, Martinez J, Minnier J, Monteblanco A, Mori M, Morrow Q, Nelson D, Ramsdill J, Rofelty A, Rogers A, Romine KA, Ryabinin P, Saultz JN, Sampson DA, Savage SL, Schuff R, Searles R, Smith RL, Spurgeon SE, Sweeney T, Swords RT, Thapa A, Thiel-Klare K, Traer E, Wagner J, Wilmot B, Wolf J, Wu G, Yates A, Zhang H, Cogle CR, Collins RH, Deininger MW, Hourigan CS, Jordan CT, Lin TL, Martinez ME, Pallapati RR, Pollyea DA, Pomicter AD, Watts JM, Weir SJ, Druker BJ, McWeeney SK, Tyner JW.

Cancer Cell

August 08, 2022

Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.

Last updated: August 31, 2022