Haematologica (Aug 2022)

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

  • Shinobu Tsuzuki,
  • Takahiko Yasuda,
  • Hiroaki Goto,
  • Naoko Maeda,
  • Koshi Akahane,
  • Takeshi Inukai,
  • Hideyuki Yamamoto,
  • Sivasundaram Karnan,
  • Akinobu Ota,
  • Toshinori Hyodo,
  • Hiroyuki Konishi,
  • Yoshitaka Hosokawa,
  • Hitoshi Kiyoi,
  • Fumihiko Hayakawa

DOI
https://doi.org/10.3324/haematol.2022.280879
Journal volume & issue
Vol. 108, no. 2

Abstract

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Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is an intractable disease and most cases harbor genetic alterations that activate JAK or ABL signaling. The commonest subtype of Ph-like ALL exhibits a CRLF2 gene rearrangement that brings about JAK1/2-STAT5 pathway activation. However, JAK1/2 inhibition alone is insufficient as a treatment, so combinatorial therapies targeting multiple signals are needed. To better understand the mechanisms underlying the insufficient efficacy of JAK inhibition, we explored gene expression changes upon treatment with a JAK1/2 inhibitor (ruxolitinib) and found that elevated BCL6 expression was one such mechanism. Upregulated BCL6 suppressed the expression of TP53 along with its downstream cell cycle inhibitor p21 (CDKN2A) and pro-apoptotic molecules, such as FAS, TNFRSF10B, BID, BAX, BAK, PUMA, and NOXA, conferring cells some degree of resistance to therapy. BCL6 inhibition (with FX1) alone was able to upregulate TP53 and restore the 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 the survival of xenografted mice. These findings provide one mechanism for the insufficiency of JAK inhibition for the treatment of CRLF2-rearranged ALL and indicate BCL6 inhibition as a potentially helpful adjunctive therapy combined with JAK inhibition.