SH/EAHP 2013 Workshop Case 285 Sara-Eloína Cuadra-Acree, MD,* Kiran Qidwai, MD,* Brit Shackley, MD,** & Imran N. Siddiqi, MD, PhD* * University of Southern California/LAC+USC Medical Center **Huntington Memorial Hospital, Pasadena, California

Clinical History Pt:41-year-old Asian femalePt:41-year-old Asian female CC:Worsening fatigueCC:Worsening fatigue Easy bruising Progressive abdominal pain PMH: Iron Deficiency AnemiaPMH: Iron Deficiency Anemia

Laboratory Studies CBC WBC:24.4 K/cummWBC:24.4 K/cumm Hb:8.9 g/dLHb:8.9 g/dL HCT:23.9%HCT:23.9% PLT:36 K/cummPLT:36 K/cumm

Molecular Analysis: FISH Negative for t(9;22) BCR/ABL fusionNegative for t(9;22) BCR/ABL fusion Negative for t(8;21) AML1/ETO [RUNX1/RUNX1T1] fusionNegative for t(8;21) AML1/ETO [RUNX1/RUNX1T1] fusion Negative for t(15;17) PML/RARA fusionNegative for t(15;17) PML/RARA fusion Negative for RARA break apart rearrangementNegative for RARA break apart rearrangement

Molecular Analysis: PCR Negative for FLT3 ITD and FLT3 D835 mutationsNegative for FLT3 ITD and FLT3 D835 mutations Negative for NPM1 mutationNegative for NPM1 mutation Negative for CEBPA mutationNegative for CEBPA mutation Negative for KIT D816V mutationNegative for KIT D816V mutation

Cytogenetics 82-84, XXXX,-1,-2,-3,-4,-7,+8,-9,-10, t(12;17)(p13;q11.2)x2, der(12)t(12;17)(p13;q11.2),+13,-15, -16, -17,-20,-21,+22[cp7]/46,XX[13]82-84, XXXX,-1,-2,-3,-4,-7,+8,-9,-10, t(12;17)(p13;q11.2)x2, der(12)t(12;17)(p13;q11.2),+13,-15, -16, -17,-20,-21,+22[cp7]/46,XX[13]

Final Diagnosis? B-LINEAGE CRITERIA:B-LINEAGE CRITERIA: –Strong CD19 with at least 1 of the following strongly expressed: CD79a, cytoCD22, CD10 or –Weak CD19 with at least 2 of the following strongly expressed: CD79a, cytoCD22, CD10 WHO (2008) CLASSIFICATION

Final Diagnosis? B-LINEAGE CRITERIA:B-LINEAGE CRITERIA: –Strong CD19 with at least 1 of the following strongly expressed: CD79a, cytoCD22, CD10 or –Weak CD19 with at least 2 of the following strongly expressed: CD79a, cytoCD22, CD10 WHO (2008) CLASSIFICATION

Final Diagnosis? MYELOID LINEAGE CRITERIA:MYELOID LINEAGE CRITERIA: –Myeloperoxidase (FCM, IHC, or cytochemistry) or –Monocytic differentiation (at least 2 of the following: NSE, CD11c, CD14, CD64, lysozyme) WHO (2008) CLASSIFICATION

Final Diagnosis? MYELOID LINEAGE CRITERIA:MYELOID LINEAGE CRITERIA: –Myeloperoxidase (FCM, IHC, or cytochemistry) or –Monocytic differentiation (at least 2 of the following: NSE, CD11c, CD14, CD64, lysozyme) WHO (2008) CLASSIFICATION

Final Diagnosis PROPOSED DIAGNOSIS Acute leukemia with mixed phenotype (B/myeloid) associated with t(12;17)(p13;q11.2)Acute leukemia with mixed phenotype (B/myeloid) associated with t(12;17)(p13;q11.2) CONSENSUS DIAGNOSIS Mixed phenotype acute leukemia (B/myeloid), associated with t(12;17)(p13;q11.2)Mixed phenotype acute leukemia (B/myeloid), associated with t(12;17)(p13;q11.2)

t(12;17)(p13;q11) This translocation rearranges: CIZ / ZNF384 (12p13)CIZ / ZNF384 (12p13) –Transcription factor TAF15 (17q11)TAF15 (17q11) –Encodes TFII subunit

Leukemia Apr;6(4): t(12;17)(p13;q21) in early pre-B acute lymphoid leukemia. Krance RA, Raimondi SC, Dubowy R, Estrada J, Borowitz M, Behm F, Land VJ, Pullen J, Carroll AJ. Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN Abstract: Structural rearrangements involving the short arm of chromosome 12 occur in 10% of cases of childhood acute lymphoid leukemia. The translocation t(12;17)(p13;q21), an uncommon 12p abnormality, was identified in five of 2620 cases (0.2%) successfully karyotyped by the Pediatric Oncology Group or St Jude Children's Research Hospital. All five cases were classified as early pre-B; however, CD10 (common acute lymphoblastic leukemia antigen) was expressed at lower levels than other markers of B-cell lineage. Two cases also expressed the myeloid-associated antigen CD33. Leukemic cells were pseudodiploid in four cases, with an extra chromosome 21 in the fifth case. All of these patients achieved complete remission. Two relapsed during subsequent therapy, and three remain in continuous remission for greater than or equal to 20 months.

Discussion 9 patients total: 8 ALL + 1 AML9 patients total: 8 ALL + 1 AML 8 ALL (early pre-B ALL phenotype)8 ALL (early pre-B ALL phenotype) –Coexpression of myeloid antigens (MPO, CD13, CD33) 1 AML (FAB M1)1 AML (FAB M1) –Auer rods, Positive for MPO, CD13, CD33 –Coexpression of strong CD19

CIZ rearrangements in 8/9 pts by FISH or PCRCIZ rearrangements in 8/9 pts by FISH or PCR –t(12;17)(p13;q11) in 6 cases –t(12;22)(p13;q12) in 2 cases –t(12;19)(p13;p13) in 1 case Clinical:Clinical: –Young adults and children –No gender predilection –No bulky disease –Leukocytosis absent or moderate –Relatively good prognosis ZNF384ID42881ch12p13.html

Diagnosis at Initial Presentation: pro-B ALLpro-B ALL Normal cytogenetics and FISH (retrospective analysis)Normal cytogenetics and FISH (retrospective analysis) Diagnosis at First Relapse (26 months later): pro-B ALLpro-B ALL Positive for t(12;17)(p13;q11) by cytogenetics and FISHPositive for t(12;17)(p13;q11) by cytogenetics and FISH Diagnosis at Second Relapse (3 months later): AML (FAB M5b acute monocytic leukemia)AML (FAB M5b acute monocytic leukemia) Positive for t(12;17)(p13;q11) by cytogeneticsPositive for t(12;17)(p13;q11) by cytogenetics

Clinical:Clinical: –Meningeal involvement with paralysis –Died from disease progression, 3 months later Conclusion:Conclusion: –Hypothesize that the t(12;17)/TAF15-ZNF384 rearrangement may have been present in an early common progenitor that is capable of differentiating along both the lymphoid and myeloid lineages.

Unique Features The t(12;17)(p13;q11) translocation has not previously been reported in cases meeting WHO criteria for mixed phenotype acute leukemia.The t(12;17)(p13;q11) translocation has not previously been reported in cases meeting WHO criteria for mixed phenotype acute leukemia. Ambiguous B/myeloid phenotypes have rarely been attributed to t(12;17)(p13;q11).Ambiguous B/myeloid phenotypes have rarely been attributed to t(12;17)(p13;q11).

References WHO. World Health Organization classification of tumours. Pathology and genetics: tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press Krance RA, Raimondi SC, Dubowy R, Estrada J, Borowitz M, Behm F, Land VJ, Pullen J, Carroll AJ. t(12;17)(p13;q21) in early pre-B acute lymphoid leukemia. Leukemia Apr;6(4): Starza R, Aventin A, Crescenzi A, Gorello P, Specchia G, Cuneo A, Angioni A, Bilhou- Nabera C, Boqué C, Foà R, Uyttebroeck A, Talmant P, Cimino G, Martelli M, Marynen P, Mecucci C, and Hagemeijer A. CIZ gene rearrangements in acute leukemia: report of a diagnostic FISH assay and clinical features of nine patients. Leukemia (2005) 19, 1696–1699. Grammatico S, Vitale A, La Starza R, Gorello P, Angelosanto N, Negulici AD, De Propris MS, Nanni M, Meloni G, Mecucci C, Foà R. Lineage switch from pro-B acute lymphoid leukemia to acute myeloid leukemia in a case with t(12;17)(p13;q11)/TAF15- ZNF384 rearrangement. Leuk Lymphoma Aug;54(8): Blood Feb 28;121(9):

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