Case Report: Precision Medicine Target Revealed by In Vitro Modeling of Relapsed, Refractory Acute Lymphoblastic Leukemia From a Child With Neurofibromatosis

Susan L Heatley; Elyse C Page; Laura N Eadie; Barbara J McClure; Jacqueline Rehn; David T Yeung; Michael Osborn; Tamas Revesz; Maria Kirby; Deborah L White

doi:10.3389/fonc.2022.851572

Case Report: Precision Medicine Target Revealed by In Vitro Modeling of Relapsed, Refractory Acute Lymphoblastic Leukemia From a Child With Neurofibromatosis

Front Oncol. 2022 Apr 20:12:851572. doi: 10.3389/fonc.2022.851572. eCollection 2022.

Authors

Susan L Heatley^{1

2

3}, Elyse C Page^{1

4}, Laura N Eadie^{1

2}, Barbara J McClure^{1

2}, Jacqueline Rehn^{1

2}, David T Yeung^{1

2

5

6}, Michael Osborn^{2

3

6

7}, Tamas Revesz^{2

3

7}, Maria Kirby^{3

7}, Deborah L White^{1

2

3

4

6

8}

Affiliations

¹ Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia.
² Faculty of Health & Medical Science, University of Adelaide, Adelaide, SA, Australia.
³ Australian & New Zealand Children's Haematology/Oncology Group, Clayton, VIC, Australia.
⁴ Faculty of Science, University of Adelaide, Adelaide, SA, Australia.
⁵ Dept of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia.
⁶ Australasian Leukaemia & Lymphoma Group, Richmond, VIC, Australia.
⁷ Dept of Haematology & Oncology, Women's & Children's Hospital, Adelaide, SA, Australia.
⁸ Australian Genomics Health Alliance, Parkville, VIC, Australia.

Abstract

Children with neurofibromatosis have a higher risk of developing juvenile myelomonocytic leukemia and acute myeloid leukemia, but rarely develop B-cell acute lymphoblastic leukemia (B-ALL). Through in-vitro modeling, a novel NF1 p.L2467 frameshift (fs) mutation identified in a relapsed/refractory Ph-like B-ALL patient with neurofibromatosis demonstrated cytokine independence and increased RAS signaling, indicative of leukemic transformation. Furthermore, these cells were sensitive to the MEK inhibitors trametinib and mirdametinib. Bi-allelic NF1 loss of function may be a contributing factor to relapse and with sensitivity to MEK inhibitors, suggests a novel precision medicine target in the setting of neurofibromatosis patients with B-ALL.

Keywords: Ph-like ALL; acute lymphoblastic leukemia; iAMP21-ALL; neurofibromatosis; relapsed/refractory ALL.

Publication types

Case Reports