Two leukemias. One shared genetic alteration. Why are the outcomes so different?

Memphis, Tennessee, August 27, 2015

Charles Mullighan, M.D., M.B.B.S., member of the Department of Pathology (right), discusses research with Michelle Churchman, Ph.D. (left)

Charles Mullighan, MD, MBBS (right) discusses research with Michelle Churchman, PhD (left)

St. Jude scientists have solved the mystery of why two types of leukemia that share the same genetic alteration behave so differently and often have quite different outcomes. The discovery offers a promising new cancer treatment strategy.

BCR-ABL1 is a well-known genetic alteration associated with several different types of leukemia. The alteration is often present in both chronic myeloid leukemia (CML) and a subtype of acute lymphoblastic leukemia (ALL) called IKZF1-mutated BCR-ABL1 ALL. Yet, these cancers behave much differently. CML, a slow-growing cancer that occurs mostly in adults, is often sensitive to targeted therapies called tyrosine kinase inhibitors, or TKIs. These drugs are a precision medicine success story. TKIs have transformed the outlook for patients with CML by targeting the abnormal BCR-ABL1 alteration.

In contrast, IKZF1-mutated BCR-ABL1 ALL is an aggressive disease that occurs in children and adults. TKIs are less effective against this high-risk ALL subtype, and patients are less likely to be cured.

Scientists have discovered how mutations in a gene called IKZF1 or IKAROS drive the development of ALL rather than CML, resulting in an aggressive leukemia that is less responsive to TKIs. In this study, researchers showed that IKZF1 mutations cause certain white blood cells with BCR-ABL1 to retain stem-cell like characteristics. That leads to a more aggressive disease and may help leukemic cells hide from targeted therapies.

“The research shows why, in this era of targeted therapies, patients with IKZF1-mutated BCR-ABL1 ALL fare so poorly,” said Charles Mullighan, MD, MBBS, Pathology. “That insight led us to a promising new treatment strategy that we are pursuing in the laboratory.”

Read the News Release.

Full citation:
Churchman ML, Low J, Qu C, Paietta EM4, Kasper LH, Chang Y1, Payne-Turner D, Althoff MJ, Song G, Chen SC, Ma J, Rusch M, McGoldrick D,Edmonson M, Gupta P, Wang YD, Caufield W, Freeman B, Li L, Panetta JC, Baker S6, Yang YL, Roberts KG, McCastlain K, Iacobucci I, Peters JL,Centonze VE7, Notta F, Dobson SM, Zandi S, Dick JE, Janke L, Peng J, Kodali K, Pagala V, Min J, Mayasundari A2, Williams RT, Willman CL,Rowe J, Luger S, Dickins RA, Guy RK, Chen T, Mullighan CG. Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia. Cancer Cell 28(3):343-56, 2015. doi: 10.1016/j.ccell.2015.07.016. 

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