Signalling input from divergent pathways subverts B cell transformation

Abstract

Malignant transformation typically involves multiple genetic lesions whose combined activity gives rise to cancer 1 . Our analysis of 1,148 patient-derived B-cell leukemia (B-ALL) samples revealed that individual mutations did not promote leukemogenesis unless they converged on one single oncogenic pathway characteristic for the differentiation stage of transformed B cells. Mutations not aligned with the central oncogenic driver activated divergent pathways and subverted transformation. Oncogenic lesions in B-ALL frequently mimic cytokine receptor signaling at the pro-B cell stage (through activation of STAT5) 2 – 4 or the pre-B cell receptor in more mature cells (through activation of ERK) 5 – 8 . STAT5- and ERK-activating lesions were frequently found but only co-occurred in ~3% of cases ( P =2.2E-16). Single-cell mutation and phosphoprotein analyses revealed the segregation of oncogenic STAT5- or ERK-activation to competing clones. STAT5 and ERK engaged opposing biochemical and transcriptional programs orchestrated by MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway came at the expense of the principal oncogenic driver and reversed transformation. Conversely, deletion of divergent pathway components accelerated leukemogenesis. Thus, persistence of divergent signaling pathways represents a powerful barrier to transformation while convergence on one principal driver defines a central event in leukemia-initiation. Pharmacological reactivation of suppressed divergent circuits strongly synergized with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to deepen treatment responses.

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression

“…Using bulk expression profiling and single-cell sequencing approaches on serial MPN and sAML patient samples, we identify aberrant overexpression of DUSP6 and downstream effector RPS6KA1 driving treatment resistance and disease progression. We target these dependencies using small molecule inhibitors BCI and BI-D1870, and through mass cytometry multiplex profiling (65). Taken together with the findings from our study, these observations highlight the promising therapeutic potential of DUSP targeting, while reinforcing the notion that DUSP6 plays context-dependent roles even within specific hematologic malignancies.…”

Expression of BCL6 in paediatric B-cell acute lymphoblastic leukaemia and association with prognosis

“…8 It has a well established role in several mature B-cell malignancies, and recent studies have implicated a role in B-ALL as well. 9,23 We report here that approximately 7% of childhood B-ALL cases were positive for the BCL6 protein. High BCL6 mRNA levels were most common among the TCF3-PBX1, Ph-like, NUTM1, MEF2D and PAX5-alt subgroups, and higher-than-median expression of BCL6 was associated with favourable EFS.…”

“…8 Recently, BCL6 has been shown to contribute significantly to the pathogenesis of acute precursor B-cell acute leukaemia. 9,23 We investigated the expression of the BCL6 protein in childhood B-ALL by collecting trephine biopsy samples from 117 paediatric B-ALL cases. The cohort was population-based, and the main B-ALL subtypes were represented at expected proportions (Table 1).…”

IGF2BP3 Associates with Proliferative Phenotype and Prognostic Features in B-Cell Acute Lymphoblastic Leukemia

“…Almost 90% of the cases showed moderate or strong positivity to IGF2BP3 , often in conjunction with a marker of activated JAK-STAT signaling (pSTAT5A-Y694). Fittingly, the expression of the BCL6 protein, which is not exhibited simultaneously with the activated JAK-STAT5 pathway [ 34 ], was absent among IGF2BP3 -positive cases. The intracellular staining pattern of IGF2BP3 was granular, possibly referring to the localization of IGF2BP3 to cytoplasmic RNP complexes, where it exerts its function on the target mRNAs.…”