Inhibition of MEK and ATR is effective in a B-cell acute lymphoblastic leukemia model driven by Mll-Af4 and activated Ras

Abstract

Infant B-cell acute lymphoblastic leukemias (B-ALLs) that harbor MLL-AF4 rearrangements are associated with a poor prognosis. One important obstacle to progress for this patient population is the lack of immunocompetent models that faithfully recapitulate the short latency and aggressiveness of this disease. Recent whole-genome sequencing of MLL-AF4 B-ALL samples revealed a high frequency of activating RAS mutations; however, single-agent targeting of downstream effectors of the RAS pathway in these mutated MLL-r B-ALLs has demonstrated limited and nondurable antileukemic effects. Here, we demonstrate that the expression of activating mutant N-RasG12D cooperates with Mll-Af4 to generate a highly aggressive serially transplantable B-ALL in mice. We used our novel mouse model to test the sensitivity of Mll-Af4/N-RasG12D leukemia to small molecule inhibitors and found potent and synergistic preclinical efficacy of dual targeting of the Mek and Atr pathways in mouse- and patient-derived xenografts with both mutations in vivo, suggesting this combination as an attractive therapeutic opportunity that might be used to treat patients with these mutations. Our studies indicate that this mouse model of Mll-Af4/N-Ras B-ALL is a powerful tool to explore the molecular and genetic pathogenesis of this disease subtype, as well as a preclinical discovery platform for novel therapeutic strategies.

Does lineage plasticity enable escape from CAR-T cell therapy? Lessons from MLL-r leukemia

“…Nonetheless, recent publications have reported that using fetal cell types and carefully regulated levels of MLL fusion oncoproteins may improve the lineage fidelity of murine MLL -r leukemia model systems. In one case, inducible Mll -AF4 knock-in models that must be kept on a mixed genetic background exhibit ~30% B-ALL with many still succumbing to AML [ 64 , 65 ] Using knock-in models from the Rabbitts’ laboratory, several groups have found that progenitors exhibit an embryonic period of sensitivity to Mll -AF4 or Mll -ENL transformation [ 66 , 67 ]. For example, Malouf and Ottersbach [ 66 ] and Barrett et al [ 68 ] reported that fetal liver lymphoid-primed progenitors exhibit a preleukemic phenotype dependent on Mll -AF4 expression but fall short of producing full-blown B-ALL.…”

Inflammation accelerates BCR-ABL1+ B-ALL development through upregulation of AID

“…Moreover, the activation of the DDR pathway is accompanied by the increase of cell proliferation, suggesting the DDR pathway disorder and DNA damage response in our mouse model. 31 Several studies have stated that the decreased DNA repair efficiency caused by DNA repair deficiencies promotes genetic instability, thus increasing individual susceptibility to cancer, 32-34 whereas others have shown that tumor cells could activate the DNA damage repair to repair damaged DNA, enhancing tumor cells’ survival even at high levels of DNA damage. 35,36 Our data prove that upregulation of AID in BCR-ABL1 + B-ALL following inflammatory stimulation is capable of increased expression of DNA damage repair genes such as Ercc1 , Lig1 , Xrcc1 , Pnkp , and Mutyh .…”

B‐cell acute lymphoblastic leukaemia: recent discoveries in molecular pathology, their prognostic significance, and a review of the current classification

“…These patients were also characterised by high residual MRD after induction 5,52 . RAS ‐mutated ALL may be susceptible to targeting through MEK inhibitors 103 . Sotorasib, recent approved for KRAS G12C‐mutated solid tumours may also serve as a paradigm for RAS inhibition in ALL 104 …”

“…5,52 RAS-mutated ALL may be susceptible to targeting through MEK inhibitors. 103 Sotorasib, recent approved for KRAS G12C-mutated solid tumours may also serve as a paradigm for RAS inhibition in ALL. 104 MYC, BCL2 and/or BCL6 MYC rearrangements involving either the light or heavy chain of the immunoglobulin gene lead to the highly proliferative Burkitt lymphoma/leukaemia.…”