Lymphoid blast transformation in an MPN with BCR-JAK2 treated with ruxolitinib: Putative mechanisms of resistance

Justin Anthony Chen, Yanli Hou, Krishna M. Roskin, Daniel A. Arber, Charles D. Bangs, Linda B. Baughn, Athena M. Cherry, Mark D. Ewalt, Andrew Z. Fire, Laure Fresard, Hutton M. Kearney, Stephen B. Montgomery, Robert S. Ohgami, Kathryn E. Pearce, Beth A. Pitel, Jason D. Merker, Jason Gotlib

Research output: Contribution to journalArticlepeer-review


The basis for acquired resistance to JAK inhibition in patients with JAK2-driven hematologic malignancies is not well understood. We report a patient with a myeloproliferative neoplasm (MPN) with a BCR activator of RhoGEF and GTPase (BCR)-JAK2 fusion with initial hematologic response to ruxolitinib who rapidly developed B-lymphoid blast transformation. We analyzed pre-ruxolitinib and blast transformation samples using genome sequencing, DNA mate-pair sequencing (MPseq), RNA sequencing (RNA-seq), and chromosomal microarray to characterize possible mechanisms of resistance. No resistance mutations in the BCR-JAK2 fusion gene or transcript were identified, and fusion transcript expression levels remained stable. However, at the time of blast transformation, MPseq detected a new IKZF1 copy-number loss, which is predicted to result in loss of normal IKZF1 protein translation. RNA-seq revealed significant upregulation of genes negatively regulated by IKZF1, including IL7R and CRLF2. Disease progression was also characterized by adaptation to an activated B-cell receptor (BCR)-like signaling phenotype, with marked upregulation of genes such as CD79A, CD79B, IGLL1, VPREB1, BLNK, ZAP70, RAG1, and RAG2. In summary, IKZF1 deletion and a switch from cytokine dependence to activated BCR-like signaling phenotype represent putative mechanisms of ruxolitinib resistance in this case, recapitulating preclinical data on resistance to JAK inhibition in CRLF2-rearranged Philadelphia chromosome-like acute lymphoblastic leukemia.

Original languageEnglish (US)
Pages (from-to)3492-3496
Number of pages5
JournalBlood Advances
Issue number17
StatePublished - Sep 14 2021

ASJC Scopus subject areas

  • Hematology


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