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Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.


ABSTRACT: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL.Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib.Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).

SUBMITTER: Roberts KG 

PROVIDER: S-EPMC4191900 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.

Roberts Kathryn G KG   Li Yongjin Y   Payne-Turner Debbie D   Harvey Richard C RC   Yang Yung-Li YL   Pei Deqing D   McCastlain Kelly K   Ding Li L   Lu Charles C   Song Guangchun G   Ma Jing J   Becksfort Jared J   Rusch Michael M   Chen Shann-Ching SC   Easton John J   Cheng Jinjun J   Boggs Kristy K   Santiago-Morales Natalia N   Iacobucci Ilaria I   Fulton Robert S RS   Wen Ji J   Valentine Marcus M   Cheng Cheng C   Paugh Steven W SW   Devidas Meenakshi M   Chen I-Ming IM   Reshmi Shalini S   Smith Amy A   Hedlund Erin E   Gupta Pankaj P   Nagahawatte Panduka P   Wu Gang G   Chen Xiang X   Yergeau Donald D   Vadodaria Bhavin B   Mulder Heather H   Winick Naomi J NJ   Larsen Eric C EC   Carroll William L WL   Heerema Nyla A NA   Carroll Andrew J AJ   Grayson Guy G   Tasian Sarah K SK   Moore Andrew S AS   Keller Frank F   Frei-Jones Melissa M   Whitlock James A JA   Raetz Elizabeth A EA   White Deborah L DL   Hughes Timothy P TP   Guidry Auvil Jaime M JM   Smith Malcolm A MA   Marcucci Guido G   Bloomfield Clara D CD   Mrózek Krzysztof K   Kohlschmidt Jessica J   Stock Wendy W   Kornblau Steven M SM   Konopleva Marina M   Paietta Elisabeth E   Pui Ching-Hon CH   Jeha Sima S   Relling Mary V MV   Evans William E WE   Gerhard Daniela S DS   Gastier-Foster Julie M JM   Mardis Elaine E   Wilson Richard K RK   Loh Mignon L ML   Downing James R JR   Hunger Stephen P SP   Willman Cheryl L CL   Zhang Jinghui J   Mullighan Charles G CG  

The New England journal of medicine 20140901 11


<h4>Background</h4>Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.<h4>Methods</h4>We performed genomic profiling of 1725 patients with precursor  ...[more]

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