Abstract 332: Targeting BCL-2 in hypodiploid acute lymphoblastic leukemia
Authors: Diaz-Flores Ernesto , Weng Julie , Akutagawa Jon , Holmfeldt Linda , Chonghaile Triona , Letai Anthony , Mullighan Charles , Braun Benjamin , Loh Mignon 
Published: May 2015

Hypodiploid Acute Lymphoblastic Leukemia (ALL), is a high-risk subtype of ALL characterized by multiple chromosomal losses with an event-free survival &lt;40%. Hypodiploidy remains an independent marker of poor outcome. In particular, outcomes for the two subtypes: low hypodiploid (32-39 chromosomes) and near haploid (24-31 chromosomes) ALL have not improved even with maximally intensive therapies such as hematopoietic stem cell transplant. Alternative therapies are therefore of urgent need.

To identify potential therapeutic targets we undertook a biochemical characterization of primary patient samples and cell lines, assessing the activation status of over 25 proteins involved in signaling pathways commonly deregulated in leukemia. Our biochemical characterization identified 1) constitutive activation of the PI3K pathway and the Bcl-2 survival pathway, and 2) accumulation of p53 that ultimately revealed that nearly 90% of low hypodiploid B-ALL patients harbor mutations in TP53 (Holmfeldt, et al., Nat. Genetics, 2013).

We then set out to explore the therapeutic potential of targeting each of the deregulated pathways. We used multiple inhibitors and a library containing 94 compounds currently in early phase trials. Our studies showed high sensitivity to Bcl-2 inhibition, using ABT 263, ABT 737 and ABT 199, and partial sensitivity to PI3K inhibition. Surprisingly, these leukemia were relatively insensitive to inhibition of the Ras/MAPK signal transduction pathway, despite a high frequency of Ras pathway genomic alterations.

Proliferation and apoptosis assays, performed in hypodiploid and non-hypodiploid leukemia cell lines (including both lymphoid and myeloid cell lines) showed a dramatic efficacy of targeting the BCL-2 pathway in hypodiploid leukemias. These results were replicated in primary patient samples xenografted into immunodeficient mice that were subjected to these drugs in vitro. A detailed biochemical characterization of the 12 members of the Bcl-2 family, together with a BH3 profiling to assess priming to apoptosis, has allowed us to determine the mechanisms underlying this sensitivity and efficacy on this leukemia.

Our overall work has provided critical insights into the essential deregulated pathways underlying the pathogenesis of hypodiploid ALL. We are now continuing our investigations to identify novel strategies to treat these patients by using in vivo xenograft models of hypodiploid leukemia. We expect that our pre-clinical studies will provide further support for the therapeutic benefit of treating these leukemias with Bcl-2 inhibitors to improve survival for these young patients who suffer unacceptably high relapse rates from current therapies.

Citation Format: Ernesto Diaz-Flores, Julie Weng, Jon Akutagawa, Linda Holmfeldt, Triona Chonghaile, Anthony Letai, Charles Mullighan, Benjamin Braun, Mignon Loh. Targeting BCL-2 in hypodiploid acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 332. doi:10.1158/1538-7445.AM2014-332