CHARLES MULLIGHAN (MEMPHIS)
TARGETING NOVEL SUBTYPES OF B CELL PROGENITOR ACUTE LYMPHOBLASTIC LEUKEMIA
Charles G. Mullighan
Department of Pathology and Hematological Malignancies Program
St. Jude Children’s Research Hospital, Memphis, TN
Genomic profiling studies conducted in the last decade, particularly transcriptomic sequencing of large
B-ALL cohorts, have shed important light into the biologic subtypes of B-ALL and their underlying
drivers. There are over 20 subtypes of B-ALL driven by distinct constellations of genetic alterations.
These include subtypes with aneuploidy or gross changes in chromosomal copy number state
(hyperdiploidy, low hypodiploidy, near haploidy, intrachromosomal amplification of chromosome 21),
chromosomal rearrangements (ETV6-RUNX1, BCR-ABL1, TCF3-PBX1, and BCL2/BCL6/MYC, DUX4,
MEF2D, NUTM1, ZNF384 and HLF rearranged) cases driven by sequence mutations (e.g. PAX5 P80R,
IKZF1 N159Y, CEBP/ZEB2 mutant), and subtypes with diverse alterations (e.g. PAX5 altered) and
subtypes phenocopying cases with canonical fusion partners (e.g. Ph-like, ETV6-RUNX1 like). The
majority of these alterations can be identified by careful analysis of transcriptomic sequencing and
thus, this approach is rapidly entering real time clinical use. Identification of these alterations has
important implications for risk stratification and targeting. For example, several of the newly identified
subtypes are associated with favorable (e.g. DUX4 and ZNF384-rearranged ALL) or unfavorable
(BCL2/BCL6/MYC, hypodiploid, MEF2D) outcome, and identification is important for initial risk
stratification. Secondly, there are emerging data that many of the subtypes may be amenable to novel
therapeutic approaches that directly target the oncogenic alterations, or pathways deregulated by
these alterations. An immediately intuitive example are tyrosine kinase inhibitors in Ph-like ALL, but
additional approaches include HDAC inhibitors in MEF2D rearranged leukemia, rexinoids and FAK
inhibitors in IKZF1 altered ALL, and FLT3 inhibitors in ZNF384-rearranged leukemia. Of these subtypes,
Ph-like leukemia represents the greatest unmet clinical need, with JAK-STAT activating alterations,
particularly CRLF2 rearrangement, comprising the majority of cases, and existing preclinical data
supporting limited efficacy of JAK inhibition, at least as monotherapy. This presentation will describe
data showing efficacy of targeted protein degradation as a potential therapeutic approach in Ph-like
ALL, as well as a conceptually attractive approach to target the alterations in zinc finger-containing
transcription factors that drive many ALL cases that fail therapy.