Co-Occurrence of <i>ETV6::RUNX1</i> and <i>P2RY8::CRLF2</i> Fusion in a Patient with Relapsed Acute B Lymphoblastic Leukemia.

B-cell acute lymphoblastic leukemias (B-ALLs) harbor recurrent chromosomal aberrations associated with prognostic and therapeutic significance. Although these major driver genetic abnormalities are generally mutually exclusive, they are rarely reported to co-occur. Here, we present the case of a child with B-ALL who suffered two relapses with short event-free intervals. The patient was found to have co-existence of translocation t(12;21) causing <i>ETV6::RUNX1</i> fusion and an interstitial deletion of chromosome X leading to <i>P2RY8::CRLF2</i> fusion. While ETV6::RUNX1 was readily detected by cytogenetic analysis of the bone marrow at the time of diagnosis, the concurrent <i>P2RY8::CRLF2</i> fusion was discovered upon molecular genetic analysis at second relapse. Notably, <i>ETV6::RUNX1</i> and <i>P2RY8::CRLF2</i> each hallmark molecular subclasses of B-ALL with distinct mutational landscapes and clinical prognoses. It is not yet known how co-existing leukemogenic chromosomal aberrations interact to modify treatment response and relapse risk of B-ALL. This case highlights the possibility that co-existing molecular aberrations may greatly impact the clinical course of B-ALL but may be under-recognized in the initial workup using standard diagnostic algorithms.