BCL6 inhibition ameliorates resistance to ruxolitinib in <i>CRLF2</i>-rearranged acute lymphoblastic leukemia

Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is intractable and mostly harbors genetic alterations that activate JAK or ABL signaling. The commonest subtype of Ph-like ALL exhibits the CRLF2 gene arrangement that brings about JAK1/2-STAT5 pathway activation. However, JAK1/2 inhibition alone is insufficient for treatment, necessitating combinatorial therapies targeting multiple signals. To better understand the mechanisms underlying the insufficient efficacy of JAK inhibition, this study explored gene expression changes upon treatment with a JAK1/2 inhibitor (ruxolitinib) and revealed BCL6 elevation as one such mechanism. Upregulated BCL6 suppressed TP53 expression along with its downstream cell cycle inhibitor p21 (CDKN2A) and proapoptotic molecules, such as FAS, TNFRSF10B, BID, BAX, BAK, PUMA, and NOXA, conferring cells in part with therapy resistance. The BCL6 inhibition (FX1) alone was able to upregulate TP53 and restore TP53 expression that ruxolitinib had diminished. In addition, ruxolitinib and FX1 concertedly downregulated MYC. As a result, FX1 treatment alone had growth-inhibitory and apoptosis-sensitizing effects, but the combination of ruxolitinib and FX1 more potently inhibited leukemia cell growth, enhanced apoptosis sensitivity, and prolonged xenografted mice survival. These findings provide one mechanism for the insufficiency of JAK inhibition for CRLF2-rearranged ALL treatment and BCL6 inhibition as a potentially helpful adjunctive therapy combined with JAK inhibition.

Venetoclax durable response in adult relapsed/refractory Philadelphia-negative acute lymphoblastic leukemia with JAK/STAT pathway alterations

“…Although few studies have investigated the efficacy of JAK inhibitors in Ph- ALL, recently Dr. Kołodrubiec and others collected preclinical and clinical pieces of evidence on the efficacy of ruxolitinib as a single agent or in combinations against Ph- ALL ( Kołodrubiec et al, 2022 ). Moreover, additional preclinical studies showed a synergistic effect of ruxolitinib in combination with BCL2 (venetoclax), BCL6 (BI3802, BI3812, and FX1) ( Tsuzuki et al, 2023 ), and LSD1 (GSK2879552) inhibitors in different ALL subtypes ( Senkevitch et al, 2018 ).…”

Small-molecule BCL6 inhibitor protects chronic cardiac transplant rejection and inhibits T follicular helper cell expansion and humoral response

“…Evidence from a study on B-cell lymphoma indicated that MLL-rearranged acute lymphoblastic leukemia could be treated with FX1, with its safety and efficacy validated at the animal level ( Hurtz et al, 2019 ). Moreover, FX1 alleviated erythromycin resistance in acute lymphoblastic leukemia, serving as an adjunctive medication in anti-tumor therapy ( Tsuzuki et al, 2022 ). In the murine sepsis model, FX1 exhibited extraordinary anti-inflammatory capacity ( Zhang et al, 2019 ).…”