Acute Lymphoid Leukemias

Question 1

IZKF1 in hematologic neoplasia

Answer 1

IZKF1 encodes IKAROS, a zinc-finger transcription factor that regulates lymphoid differentiation and is essential for both B- and T-lymphopoiesis.

It is found inactivated in B acute lymphoblastic leukemia, and is a negative prognostic factor in both pediatric and adult B-ALL. Experimental deletion of exon 4 or exon 6 (containing key DNA-binding domains) results in B cell maturation arrest.

Present in 15% of pediatric B-ALL and 40-50% of adult B-ALL, with elevated rates in BCR-ABL1 translocated B-ALL (85%) and BCR-ABL1-like B-ALL (70%).

Rarely present in T-ALL, but occur in about 13% of EP-T-ALL.

Common pathogenic variants include deletion of the whole gene (both monoallelic and biallelic) as well as deletions involving exons 4-7, which produce dominant negative proteins which lack DNA-binding capacity but still contain the dimerization domain in exon 8. There appears to be haploinsufficiency with monoallelic gene deletion.

Rarely, IZKF1 fusions are seen, including IZKF1::NPM1, IZKF1::SETD5, and SETD5::IZKF1, however the pathogenicity of these fusions remains unclear.

Question 2

Hyperdiploid B-ALL

Answer 2

One of the favorable molecular subtypes of B-ALL

Question 3

ETC6-RUNX1 B-ALL

Answer 3

One of the favorable molecular subtypes of B-ALL

Question 4

iAMP21 B-ALL

Question 5

MLL gene-rearranged B-ALL

Question 6

Hypodiploid B-ALL

Question 7

Ph+ B-ALL

Question 8

Ph-like B-ALL

Answer 8

Family of B-ALLs with a gene expression profile similar to that of Ph+ B-ALL, but lacking a definitive Philidelphia chromosome / BCR-ABL1 fusion protein.

Have a prognosis similar to that of Ph+ B-ALL.

Question 9

Most common drivers in EP-T-ALL

Answer 9

FLT3, JAK1, JAK3, IL7R