Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia

Abstract

SUMMARY Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL, and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2 and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2 negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy.

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

“…Over the last decade, studies utilizing microarray analysis of gene expression, DNA copy-number alterations, and next-generation sequencing have provided major insights into the pathogenesis and clinical behavior of ALL. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Most ALL genomes harbor sequence and structural DNA alterations involving coding genes, as well as alterations of noncoding elements such as noncoding RNAs 23 and enhancer elements. 24,25 Here, we consider results from these studies in several categories: (1) identification of new subtypes of ALL that lack recurring gross chromosomal alterations; (2) characterization of the constellations of genetic alterations that define each ALL subtype; (3) the relationship between genetic alterations, clonal heterogeneity, and relapse; (4) identification of inherited genetic variants and mutations linked to ALL susceptibility and outcome; (5) and translating new discoveries to improved diagnostic, prognostic, and precision medicine approaches.…”

“…41 Ph-like ALL is characterized by a diverse range of genetic alterations that dysregulate cytokine receptor and tyrosine kinase signaling (Table 3 and Figure 3). 14,22 Analysis of over 1700 cases of B-ALL identified several types of kinase alteration in Ph-like ALL: rearrangements of CRLF2 (47% of cases), rearrangements of ABL-class tyrosine kinase genes (12%), rearrangements of JAK2 (7%) and EPOR (10%), mutations activating Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling (11%) and Ras (6%), and less common kinase alterations (NTRK3 and PTK2B).…”

“…14,22 Multiple fusion partners have been identified, each involving the kinase as the downstream partner and preserving an intact kinase domain ( Figure 4). JAK2 is rearranged to at least 14 different partner genes in Ph-like ALL.…”

“…EPOR rearrangements include reciprocal or cryptic translocations with immunoglobulin and other loci (eg, IGH and IGK) that deregulate receptor expression and also truncate EPOR, causing increased JAK-STAT signaling. 14,22 CRLF2 encodes cytokine receptor like factor 2, also known as the thymic stromal-derived lymphopoietin receptor (TSLPR) that forms a heterodimeric receptor with the interleukin-7 receptor a chain (IL7Ra) for thymic stromal lymphopoietin (TSLP). CRLF2 is rearranged to the immunoglobulin heavy chain locus (IGH-CRLF2) or by a deletion upstream of CRLF2 that results in expression of P2RY8-CRLF2.…”

Therapy of pediatric ALL: from Bowie to Obama

“…Moreover, outcome differences are influenced by risk group, treatment, and ethnicity. 4 In addition, the definition of Ph-like ALL varies 2,3 : we described Ph-like ALL using formal gene expression prediction algorithms 7 So, what does all this mean, and which alterations should be identified to refine risk stratification and tailoring of therapy? We think that focusing on the prognostic import of individual lesions is missing the forest for the trees.…”