Background: Ph-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of ALL in both children and adults (Roberts, NEJM 2014; Roberts, JCO 2017; Jain, Blood 2017). Inherited GATA3 variants (rs3824662) have been described in higher frequency in children with Ph-like ALL (Perez-Andreu, Nat Genetics 2013). The frequency and clinical correlation of this genetic variant in adult patients with Ph-like ALL is unknown.
Methods: Ph-like ALL status was defined by gene expression profiling using either U133 Plus 2.0 microarrays as previously described (Roberts, NEJM 2014), or a customized Taqman low-density array card. CRLF2 rearrangement (IGH - CRLF2 or P2RY8 - CRLF2) was confirmed using fluorescence-in-situ-hybridization (FISH). Genome-wide SNP genotyping was performed using Affymetrix SNP 6 or Illumina Omni2.5 array. Genetic ancestry was inferred by STRUCTURE using genotypes at 30,000 randomly selected SNPs. Association of GATA3 rs3824662 genotype with Ph-like ALL and/or CRLF2 rearrangement was evaluated by logistic regression, after adjusting for genetic ancestry as appropriate.
Results: A total of 187 newly diagnosed B-ALL patients at MD Anderson Cancer Center (MDACC) were evaluated for Ph-like gene expression profile (Figure 1). Fifty-three patients had Ph-like ALL (30 CRLF2 rearranged; 23 non- CRLF2). We performed analyses for GATA3 rs3824662 variant in those with available samples (n=85). The rs3824662 AA genotype was identified in 20 of 42 (47.6%) patients with Ph-like ALL vs. 2 of 43 (4.6%) patients without Ph-like ALL (P= 4.215x10-6). The risk allele frequency (RAF) was 65.5% among the Ph-like ALL patients vs. 25.5% among the non-Ph-like ALL patients (P= 0.00056) (Figure 2). The rs3824662 AA genotype was particularly over-represented patients with CRLF2 rearranged Ph-like ALL (56%) vs. non- CRLF2 rearranged Ph-like ALL (35%). The RAF was 78% in the CRFL2 rearranged Ph-like ALL, compared to 47% in non- CRFL2 rearranged Ph-like ALL (Figure 2). Among the Ph-like ALL, GATA3 rs3824662 A allele was over-represented in Ph-like ALL with CRLF2, JAK2, or IKZF1 abnormalities (up to 80%). GATA3 rs3824662 A allele was significantly more common in US Hispanics than individuals of non-Hispanic background (P= 0.00055), as defined by Native American genetic ancestry. We hypothesize that GATA3 regulates CRFL2 transcription, and this may in turn leads to CRLF2 overexpression (Yang et al., ASH 2017 submitted).
Conclusions: Similar to pediatric patients, GATA3 SNP rs3824662 is associated with susceptibility to Ph-like ALL in adults, with a preponderance of ALL patients with CRLF2 abnormalities. There is significant over-representation of this germline genetic variant in patients of Hispanic background, which may in part explain the high incidence of Ph-like ALL in this population.
Jain: Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jabbour: Bristol-Myers Squibb: Consultancy. Kantarjian: Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Delta-Fly Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding. Mullighan: Amgen: Consultancy; Loxo Oncology: Research Funding.
Asterisk with author names denotes non-ASH members.